Process for making 5-substituted pyrazoles

ABSTRACT

This invention relates to a novel process of preparing selected 5-substituted pyrazoles useful as p38 kinase and COX-2 inhibitors.

This application is a CON of Ser. No. 09/922,819 Aug. 6, 2001 U.S. Pat.No. 6,482,955 which is a CON of Ser. No. 09/772,743 Jan. 30, 2001 U.S.Pat. No. 6,342,608 which is a DIV of Ser. No. 09/633,726 Aug. 7, 2000U.S. Pat. No. 6,242,612 which is a DIV of Ser. No. 09/442,971 Nov. 18,1999 U.S. Pat. No. 6,143,892 which claims benefit of Ser. No. 60/109,177Nov. 20, 1998.

FIELD OF THE INVENTION

This invention relates to the preparation of selected substitutedheterocycles that are useful for the treatment of inflammatory diseases.In particular, the application discloses a method for the preparation ofa number of substituted heterocycles that are p38 kinase and COX-2inhibitors. The heterocycles described herein may be useful for thetreatment of other disease states.

RELATED ART

Dithietanes have previously been prepared from selected 1,3-dicarbonylcompounds. These so-called active methylene compounds include esters ofmalonic acid, beta-keto esters, and 1,3-diketones. [(1) Katagiri, N.;Ise, S.; Watanabe, N.; Kaneko, C., Chem. Pharm. Bull. 1990, 12,3242-3248. (2) Okajima, N.; Okada, Y., J. Heterocyclic Chem. 1990, 27,567-574.] Selected dithioles derived from esters of malonic acid havebeen described as inhibitors of cancer metastasis. [Onaka, S.; Gokou, S.Japanese Patent Application JP 10212239 1998. Certain(1,2,4-triazolyl)ketene S,S-acetals have been previously reported toreact with hydrazine to afford pyrazolyl-1,2,4-triazoles. [Huang, Z. N.;Li, Z. M., Synth. Commun. 1996, 26, 3115-3120.] Condensation of selectedcyclic alpha-oxo-alpha-(1,2,4-triazol-1-yl)ketene N,S-acetals withhydrazine afforded 5-mercaptoalkylamino- and5-anilinoalkylthiopyrazolyl-1,2,4-triazoles. [(1) Huang, Z. N.; Li, Z.M., Heterocycles 1995, 41, 1653-1658.] Historically, 3-amino-pyrazoleshave been prepared by a sulfur extrusion rearrangement from6H-1,3,4-thiadiazine derivatives in the presence of base. [(1) Beyer,H.; Honeck, H.; Reichelt, L., Justus Liebigs Ann. Chem. 1970, 741, 45.(2) Schmidt, R. R.; Huth, H., Tetrahedron Lett., 1975, 33. (3) Pfeiffer,W. D.; Dilk, E.; Bulka, E., Synthesis, 1977, 196-198.] This experimentalprotocol normally works adequately for the preparation of simple3-amino-4-pyrazoles. The 6H-1,3,4-thiadiazine derivatives are in turnprepared by the condensation of alpha-chloroketones withthiosemicarbazides. This in turn necessitates preparing both therequisite alpha-chloroketone and thiosemicarbazide. In general, theaforementioned methodology was not useful for the preparation of theanti-inflammatory pyrazoles of the present invention. The knownliterature methods for the preparation of pyrazoles described abovesuffered from poor chemical yields and often gave mixtures of productsthat necessitated a careful chromatographic separation. In a number ofinstances, no desired pyrazole at all could be obtained using themethods disclosed in the literature. The present method has theadvantage of being more direct (fewer steps) and provides the desiredpyrazoles in significantly higher yield and with higher purity. Inaddition, the present method has the added advantage that it does notrely on the preparation of unstable alpha-chloroketones. Frequently thealpha-chloroketones suffered de-chlorination upon treatment withthiosemicarbazides.

SUMMARY OF THE INVENTION

This invention encompasses a process for the preparation of selectedsubstituted pyrazole derivatives of the Formula A and B useful for thetreatment of inflammatory diseases, wherein Y is SR₆, NR₄R₅, or OR₆.

DETAILED DESCRIPTION OF THE INVENTION

The invention encompasses a process for making a compound of Formula Iaor Ib

wherein:

R₁ is selected from the group consisting of hydrogen, alkyl, O-alkyl,O-cycloalkyl, cycloalkyl, cycloalkenyl, and a 5 or 6 memberedheterocycle substituted with one or more substituents selected from thegroup consisting of C₁₋₃ alkyl, halo, OH, O-alkyl, cyano, CF₃, OCF₃ andsubstituted phenyl wherein the substituents are selected from the groupconsisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃,alkyl, SO₂CH₃, SO₂NH₂, SO₂NHCOalkyl, SO₂NHCOalkyl, alkenyl, and alkynyl;

R₂ is selected from the group consisting of pyridyl, pyrimidyl,triazinyl, hydrogen, halo, alkyl, and mono- or di-substituted 6-memberedheterocycle wherein the substituent is selected from the groupconsisting of hydrogen, halo, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, alkyl,alkylamino, dialkylamino, and mono or di-substituted phenyl optionallysubstituted from the group selected from hydrogen, halo, alkoxy,alkylthio, cyano, CF₃, OCF₃, alkyl, alkylamino, and dialkylamino;

R₃ is selected from the group selected from hydrogen, alkyl, and phenyl,wherein all but hydrogen may optionally be substituted by one or more ofthe group consisting of SO₂CH₃, halo, alkyl, O-alkyl, S-alkyl, cyano,CF₃, OCF₃ and SO₂NH₂;

R₄ is selected from the group consisting of alkyl, phenyl, cycloalkyland heterocyclyl optionally substituted by one or more of the groupconsisting of OH, NH₂, SH, O-alkyl, NHR₇, N(R₇)₂, alkoxycarbonyl, acyland halo;

R₅ is selected from the group consisting of alkyl, phenyl, cycloalkyland heterocyclyl optionally substituted by one or more of the groupconsisting of OH, NH₂, SH, S-alkyl, O-alkyl, NHR₇, N(R₇)₂, CO₂H, halo,alkoxycarbonyl, acyl, heterocyclyl, cycloalkyl, heterocycloalkyl, andheterocyclyl;

R₄ and R₅ taken together may form a ring selected from the groupconsisting of morpholine, aziridine, thiomorpholine, piperidine,piperazine, and N′-piperazine;

R₇ is selected from the group consisting of alkyl and cycloalkyl;

comprising:

reacting an organometallic reagent of the formula R₂CH₂M wherein M isselected from the group consisting of Li, Na, K, and Mg, with anactivated form of a carboxylic acid to produce a ketone of Formula Ic;

treating the ketone of Formula Ic with a mixture of carbon disulfide anddihalomethane such as dibromomethane or iodochloromethane in thepresence of a base and a solvent to produce the dithietane derivative ofFormula Id;

reacting the dithietane derivative of Formula Id with an amine offormula R₄—NH—R₅ to produce the thioamide of Formula Ie, If, or Ig;

condensing the thioamide of Formula Ie, If or Ig with hydrazine orsubstituted hydrazine.

In another embodiment of the invention is the process of makingcompounds of Formula IIa or IIb

wherein:

R₁ is selected from the group consisting of hydrogen, alkyl, O-alkyl,O-cycloalkyl, cycloalkyl, cycloalkenyl, and 5 or 6 membered heterocyclesubstituted with one or more substituents selected from the groupconsisting of C₁₋₃ alkyl, halo, OH, O-alkyl cyano, CF₃, OCF₃, andsubstituted phenyl wherein the substituents are selected from one ormore of the group consisting of hydrogen, halo, alkoxy, alkylthio,cyano, CF₃, OCF₃, alkyl, SO₂CH₃, SO₂NH₂, SO₂NHCOalkyl, SO₂NHCOalkyl,alkenyl, and alkynyl;

R₂ is selected from the group consisting of pyridyl, pyrimidyl,triazinyl, hydrogen, halo, alkyl, and mono- or di-substituted 6-memberedheterocycle wherein the substituent is selected from the groupconsisting of hydrogen, halo, O-alkyl, S-alkyl, cyano, CF₃, OCF₃, alkyl,alkylamino, dialkylamino, and mono or di-substituted phenyl optionallysubstituted from the group selected from hydrogen, halo, alkoxy,alkylthio, cyano, CF₃, OCF₃, alkyl, alkylamino and dialkylamino;

R₃ is selected from the group selected from hydrogen, alkyl, and phenylwherein all but hydrogen may be substituted by one or more of the groupconsisting of SO₂CH₃, halo, alkyl, O-alkyl, S-alkyl, cyano, CF₃, OCF₃,and SO₂NH₂;

R₆ is selected from the group consisting of hydrogen, alkyl, phenyl,cycloalkyl and heterocyclyl which may be optionally substituted by oneor more of the group consisting of phenyl, substituted phenyl,alkoxycarbonyl, acyl, halo, OH, NH₂, NHR₃, N(R₃)₂, and cyano,cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring;

comprising:

reacting an organometallic reagent of the formula R₂CH₂M wherein M isselected from the group consisting of Li, Na, K, and Mg, with anactivated form of a carboxylic acid to produce a ketone of Formula Iic;

treating the ketone of Formula IIc with a mixture of carbon disulfideand dihalo methane such as dibromomethane or iodochloromethane in thepresence of a base and a solvent to produce the dithietane derivative ofFormula IId;

reacting the dithietane derivative of Formula IId with NaOR₆ to produceFormula IIe;

condensing Formula IIe with hydrazine or substituted hydrazine.

In another embodiment of the invention is the process of makingcompounds of Formula IIIa or IIIb

wherein:

R₁ is selected from the group consisting of hydrogen, alkyl, O-alkyl,O-cycloalkyl, cycloalkyl, cycloalkenyl, and 5 or 6 membered heterocyclesubstituted with one or more of the substituents selected from the groupconsisting of alkyl, halo, OH, O-alkyl, cyano, CF₃, OCF₃, andsubstituted phenyl wherein the substituents are selected from the groupconsisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF₃, OCF₃,alkyl, SO₂CH₃, SO₂NH₂, SO₂NHCOalkyl, SO₂NHCOalkyl, alkenyl, and alkynyl;

R₂ is selected from the group consisting of pyridyl, pyrimidyl,triazinyl, hydrogen, halo, alkyl, mono- or di-substituted 6-memberedheterocycle wherein the substituent is selected from the groupconsisting of one or more hydrogen, halo, O-alkyl, S-alkyl, cyano, CF₃,OCF₃, alkyl, alkylamino, dialkylamino, and mono or di-substituted phenylsubstituted from the group selected from hydrogen, halo, alkoxy,alkylthio, cyano, CF₃, OCF₃, alkyl, alkylamino, and dialkylamino;

R₃ is selected from the group selected from hydrogen, alkyl, phenyl ofwhich all but hydrogen may be optionally substituted by one or more ofthe group consisting of SO₂CH₃, halo, alkyl, O-alkyl, S-alkyl, cyano,CF₃, OCF₃, and SO₂NH₂,

R₆ is selected from the group consisting of hydrogen, alkyl, phenyl,cycloalkyl, and heterocyclyl which may be optionally substituted by oneor more of the group consisting of phenyl, substituted phenyl, halo,alkoxycarbonyl, acyl, OH, NH₂, NHR₃, N(R₃)₂, and cyano, cycloalkyl,heterocycloalkyl, and 3-7 membered heterocycle ring;

comprising:

reacting an organometallic reagent of the formula R₂CH₂M wherein M isselected from the group consisting of Li, Na, K, and Mg, with anactivated form of a carboxylic acid to produce a ketone of Formula IIIc;

treating the ketone of Formula IIIc with a mixture of carbon disulfideand dihalomethane such as iodochloromethane or dibromomethane in thepresence of a base and a solvent to produce the dithietane derivative ofFormula IIId;

reacting the dithietane derivative of Formula IIId with R₃NHNH₂ toproduce a heterocycle of the formula IIIe or IIIf and their tautomers;

reacting the heterocycle of the formula IIIe or IIIf with an activatedform of R₆ in the presence of a base and a solvent.

The term “alkyl”, alone or in combination, means an acyclic alkylradical containing from 1 to about 10, or from 1 to about 8 carbon atomsor 1 to about 6 carbon atoms. Said alkyl radicals may be optionallysubstituted. Examples of such radicals include methyl, ethyl,chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl,cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl,iso-amyl, hexyl, octyl and the like.

The term “alkenyl” refers to an unsaturated, acyclic hydrocarbon radicalin so much as it contains at least one double bond. Such radicalscontaining from about 2 to about 10 carbon atoms, or from about 2 toabout 8 carbon atoms or 2 to about 6 carbon atoms. Said alkenyl radicalsmay be optionally substituted. Examples of suitable alkenyl radicalsinclude propylenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl,pentenylen-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl,3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radicalin so much as it contains one or more triple bonds, such radicalscontaining about 2 to about 10 carbon atoms, or about 2 to about 8carbon atoms or 2 to about 6 carbon atoms. Said alkynyl radicals may beoptionally substituted. Examples of suitable alkynyl radicals includeethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl,pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl,hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

The term “cyano” radical denotes a carbon radical having three of fourcovalent bonds shared by a nitrogen atom.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkenyl” denotes linear or branched radicals having from 1to about 10 carbon atoms and having one or more double bonds wherein anyone or more of the alkenyl carbon atoms is substituted with halo asdefined above. Dihaloalkenyl radicals may have two or more of the samehalo atoms or a combination of different halo radicals andpolyhaloalkenyl radicals may have more than two of the same halo atomsor a combination of different halo radicals.

The term “heterocyclyl” embraces saturated, partially saturated andunsaturated heteroatom-containing ring-shaped radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. Examplesof saturated heterocyclic radicals include saturated 3 to 7-memberedheteromonocylic group containing 1 to 4 nitrogen atoms[e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated3 to 7-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to7-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partiallysaturated heterocyclyl radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclicradicals, also termed “heteroaryl” radicals, include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.]tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturatedcondensed heterocyclic group containing 1 to 5 nitrogen atoms, forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclicgroup containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.;unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl,etc.] and the like. The term also embraces radicals where heterocyclicradicals are fused with aryl radicals. Examples of such fused bicyclicradicals include benzofuran, benzothiophene, and the like. Said“heterocyclyl” group may have 1 to 3 substituents as defined below.Heterocyclic radicals include five to ten membered fused or unfusedradicals. Non-limiting examples of heterocyclic radicals includepyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl,oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl,tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl,2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl,isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl,1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazonyl,quinolinyl, tetraazolyl, and the like.

The term “cycloalkyl” embraces radicals having three to ten carbonatoms. Cycloalkyl radicals are “lower cycloalkyl” radicals having threeto seven carbon atoms. Examples include radicals such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term“cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals.Cycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals havingcycloalkyl radicals attached to alkyl radicals having one to six carbonatoms. Examples of such radicals include cyclohexylhexyl.

The term “cycloalkenyl” embraces radicals having three to ten carbonatoms and one or more carbon-carbon double bonds. Cycloalkenyl radicalsare “lower cycloalkenyl” radicals having three to seven carbon atoms.Examples include radicals such as cyclobutenyl, cyclopentenyl,cyclohexenyl and cycloheptenyl.

The term “halocycloalkyl” embraces radicals wherein any one or more ofthe cycloalkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohalocycloalkyl, dihalocycloalkyl andpolyhalocycloalkyl radicals. A monohalocycloalkyl radical, for oneexample, may have either a bromo, chloro or a fluoro atom within theradical. Dihalo radicals may have two or more of the same halo atoms ora combination of different halo radicals and polyhalocycloalkyl radicalsmay have more than two of the same halo atoms or a combination ofdifferent halo radicals. Halocycloalkyl radicals are “lowerhalocycloalkyl” radicals having three to about eight carbon atoms.Examples of such halocycloalkyl radicals include fluorocyclopropyl,difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, anddichlorocyclopropyl. The term “halocycloalkenyl” embraces radicalswherein any one or more of the cycloalkenyl carbon atoms is substitutedwith halo as defined above. Specifically embraced aremonohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenylradicals. The term “halocycloalkoxy” also embraces cycloalkoxy radicalshaving one or more halo radicals attached to the cycloalkoxy radical,that is, to form monohalocycloalkoxy, dihalocycloalkoxy, andpolycycloalkoxy radicals.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. Alkylthio radicals are “lower alkylthio” radicals having one tosix carbon atoms. An example of “lower alkylthio” is methylthio(CH₃—S—). The term “alkylsulfinyl” embraces radicals containing a linearor branched alkyl radical, of one to ten carbon atoms, attached to adivalent —S(═O)— atom.

The terms “alkoxy” and “alkoxyalkyl” embrace linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy radical. The term “alkoxyalkyl” alsoembraces alkyl radicals having one or more alkoxy radicals attached tothe alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkylradicals. Alkoxy radicals are “lower alkoxy” radicals having one to sixcarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy alkyls. The “alkoxy” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, andfluoropropoxy.

The term “substituted phenyl” embraces a phenyl moiety substituted atone or more carbons with one or more suitable substituent. Saidsubstituents include alkyl, alkenyl, alkynyl, O-alkyl, S-alkyl,O-alkenyl, S-alkenyl, halo, cyano, CF₃, OCF₃, SO₂NH₂, SO₂CH₃, OH, NH₂,N, S, O, and the like.

Scheme 1 shows a process for synthesis of selected 5-amino-pyrazoles.Treatment of 1 with a base such as sodium bis(trimethylsilyl)amidegenerates the corresponding organometallic. This organometallic reagentis then treated with an ester 2 in a suitable solvent such astetrahydrofuran to afford the desired ketone 3. Treatment of ketone 3with a mixture of carbon disulfide, dihalomethane, and a base such aspotassium carbonate in a suitable solvent such as acetone provides thekey dithietane compound 4. The dithietane compound 4 may then be reactedwith an appropriate amine with or without heating in an acceptablesolvent such as toluene or acetonitrile to make the thioamide compound5. Thioamide compound 5 is treated with a mono-substituted hydrazine (6)or hydrazine (6, R═H) in an appropriate solvent such as tetrahydrofuranor an alcohol with or without heating to produce pyrazoles 7 and 8. Inthe case of hydrazine (6, R═H) the pyrazoles (7 and 8, R₃═H) thusproduced are tautomers.

The dithietane 4 is added to a solution of a sodium or potassiumalkoxide in THF. The alkoxide may be generated by treating an alcohol,in THF, with a suitable base, such as sodium hydride, NaHMDS, or KHMDS.The reaction mixture is allowed to stir from 4 to 72 hours at roomtemperature. The resulting thionoester 9 is allowed to react withhydrazine, or its hydrate, in ethanol, methanol, or THF at roomtemperature for 2-18 hours to generate the pyrazole products 10.

To the dithietane 4 in toluene is added an amine, such as thiomorpholineand heated from 80-110° C. The resulting thioamide 11 may be isolated orused directly in the next reaction step. To the thioamide in THF isadded a suitable base, such as potassium t-butoxide and the resultingthiol anion alkylated with iodomethane. The resulting intermediate 12can be cyclized with hydrazine, in a solvent, such as THF or ethanol, togenerate the pyrazole 13.

The dithietane 4 in a suitable solvent, such as THF or ethanol, isallowed to react with hydrazine, or its hydrate, at room temperature upto the reflux temperature of the solvent to generate the thiopyrazole14. The thiol group may be alkylated with a variety of alkylatingagents, such as alkyl halides or Michael acceptors, including; methylchloroacetate, ethyl acrylate, and benzyl bromide, in the presence of asuitable base such as potassium carbonate, sodium ethoxide ortriethylamine in a solvent such as DMF or ethanol to generate thedesired pyrazoles 15.

Pyrazoles, such as 16, containing acid labile amine protecting groupsmay be treated with a suitable acid catalyst, such as TFA indichloromethane or HCl in ethanol or dioxane. The resulting amine 17 canthen be acylated or alkylated in a straightforward fashion using asuitable base, such as potassium carbonate or triethylamine, with areagent, such as for example; acetyl chloride or methyl iodide. Inaddition, N-methylation can be performed directly, using formaldehydeand formic acid in ethanol/water at reflux to give the desired pyrazoles18.

Pyrazoles containing base labile esters, such as 19, may be treated witha suitable base, such as, NaOH to generate the free acid 20. Theresulting acid can then aminated in a straightforward fashion using asuitable coupling reagent, such as EDC or TBTU, with or withoutcatalysts, such as HOBt or N-hydroxysuccinimide, and an appropriateamine. In addition, amidation can be performed directly, by treating themethyl ester with an appropriate amine, for example N-methylpiperazine,in a suitable solvent such as DMF or methanol, at a temperature fromroom temperature up to reflux to generate the desired pyrazoles 21.

The following examples are provided to illustrate the present inventionand are not intended to limit the scope thereof. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used to preparethese compounds.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding descriptions, utilize the present invention toits fullest extent. Therefore the following preferred specificembodiments are to be construed as merely illustrative and notlimitative of the remainder of the disclosure in any way whatsoever.Compounds containing multiple variations of the structural modificationsillustrated in the preceding schemes or the following Examples are alsocontemplated.

The starting materials which are required for the above processes hereindescribed are known in the literature or can be made by known methodsfrom known starting materials.

EXAMPLE 1

1-[5-(3-Tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl-4-methylpiperazine

Step 1. Preparation of 1-tolyl-2-(4-pyridyl)ethanone

Methyl 3-methylbenzoate (6.0 g, 40 mmol), tetrahydrofuran (50 mL), and4-picoline (4.1 g, 44 mmol) were stirred at −78° C. under an atmosphereof nitrogen. Sodium bis(trimethylsilyl)amide 1.0 M in THF (88 mL, 88mmol) was added dropwise. The mixture was allowed to warm to roomtemperature and stir for 16 h when it was poured into saturated aqueoussodium bicarbonate solution. The mixture was then extracted with ethylacetate (3×50 mL). The combined organics were washed with brine (2×50mL), dried over magnesium sulfate, and concentrated. The product wasrecrystallized from ethyl acetate/hexane to yield a light yellow solid(5.7 g, 67%): mp 118.0-119.0° C. ¹H NMR (acetone-d₆/300 MHz) 8.50 (m,2H), 7.90 (m, 2H), 7.44 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H), 2.41 (s,3H). ESHRMS m/z 212.1067 (M+H, C₁₄H₁₃NO requires 212.1075).

Anal. Calc'd for C₁₄H₁₃NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.54;H, 6.30; N, 6.56.

Step 2. Preparation of1-(3-tolyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridyl)ethanone

1-Tolyl-2-(4-pyridyl)ethanone (4.22 g, 20 mmol), acetone (100 mL),potassium carbonate (8.3 g, 60 mmol), carbon disulfide 4.56 g, 60 mmol),and dibromomethane (10.43 g, 60 mmol) were stirred at room temperaturefor 16 h. Water (100 mL) was added and the mixture was extracted withethyl acetate (3×50 mL). The combined organic extracts were washed withbrine (2×50 mL), dried over magnesium sulfate and concentrated. Thiscrude material was purified by either flash column chromatographyeluting with ethyl acetate: hexane or crystallization from ethylacetate/hexane to yield a yellow solid (4.8 g, 80%): mp 178.6-179.2° C.¹H NMR (acetone-d₆/300 MHz) 8.47 (m, 2H), 7.08 (m, 6H), 4.37 (s, 2H),2.21 (s, 3H). ESHRMS m/z 300.0521 (M+H, C₁₆H₁₄NOS₂ requires 300.0517).

Anal. Calc'd for C₁₆H₁₃NOS₂: C, 64.18; H, 4.38; N, 4.68. Found: C,64.08; H, 4.25; N, 4.62.

Step 3. Preparation of1-[3-(3-tolyl)-3-oxo-2-(4-pyridyl)-1-thiopropyl]-4-methylpiperazine

1-(3-tolyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridyl)ethanone (3.0 g, 10mmol), N-methylpiperazine (5.0 g, 50 mmol), and toluene (50 mL) wereheated to reflux using a Dean-Stark apparatus for 1 to 3 h. The reactionwas allowed to cool to room temperature and was concentrated to drynessunder high vacuum. This thick, oily material was crystallized from ethylacetate/hexane (2.9 g, 82%): mp 124.8-125.8° C. ¹H NMR (acetone-d₆/300MHz) 8.57 (m, 2H), 7.75(m, 2H), 7.54 (m, 2H), 7.37 (m, 2H) 6.54 (s, 1H),4.27 (m, 2H), 4.19 (m, 1H), 3.83 (m, 1H), 2.47-2.28 (m, 6H), 2.22 (s,3H), 2.17 (m, 1H). ESHRMS m/z 354.1669 (M+H, C₂₀H₂₄N₃OS requires354.1640).

Anal. Calc'd for C₂₀H₂₃N₃OS: C, 67.96; H, 6.56; N, 11.89. Found: C,67.79; H, 6.66; N, 11.88.

Step 4. Preparation of1-[5-(3-tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl-4-methylpiperazine

1-[3-(3-tolyl)-3-oxo-2-(4-pyridyl)-1-thiopropyl]-4-methylpiperazine(1.06 g, 3 mmol), tetrahydrofuran (50 mL), and hydrazine (15 mL, 15mmol, 1.0 M in THF were stirred at room temperature for 16 h. A whitesolid was collected by filtration. Purification when necessary was bytrituration or recrystallization (0.98 g, 97%): mp 261.9-262.0° C. ¹HNMR (DMSO-d₆/300 MHz) 12.6 (brs, 1H), 8.42 (m, 2H), 7.2 (m, 4H), 7.12(s, 1H), 7.0 (m, 1H), 2.86 (m, 4H), 2.34 (m, 4H) 2.25 (s, 3H), 2.16 (s,3H). ESHRMS m/z 334.2049 (M+H, C₂₀H₂₄N₅ requires 334.2032).

Anal. Calc'd for C₂₀H₂₃N₅: C, 72.04; H, 6.95; N, 21.00. Found: C, 71.83;H, 7.06; N, 20.83.

EXAMPLE 2

Step 1. 1-(4-chlorophenyl)-2-(4-pyridyl)ethanone was prepared accordingto the procedure used in example 1, step 1, Yield: 74%, yellow solid, mp95.5-97.3° C. ¹H-NMR (DMSO-d₆/300 MHz) 8.57 (br d, 2H), 7.92 (d, 2H),7.46 (d, 2H), 7.20 (d, 2H), 4.28 (s, 2H). ESLRMS m/z 232 (M+H).

Step 2. To a solution of 1-(4-chlorophenyl)-2-(4-pyridyl)ethanone (70.0g, 0.3 mol), dibromomethane (200 mL) and carbon disulfide (25.9 g, 0.34mol) in acetone (800 mL) was added potassium carbonate (83.0 g, 0.6mol). The reaction mixture was stirred at room temperature for 24 h. Anadditional two equivalents of potassium carbonate and one equivalent ofcarbon disulfide was added and the stirring was continued for another 24h. Solvent was removed and the residue was partitioned betweendichloromethane and water. The organic layer was washed with brine,dried over magnesium sulfate and filtered. The filtrate was concentratedand the crude product was stirred with 1 L of a mixture of ethyl acetateand ether (1:9) to give 78.4 g, 82% of pure product as a yellow solid,mp 185.3-185.4° C. ¹H NMR (acetone-d₆/300 MHz) 8.49 (m, 2H), 7.31 (m,4H), 7.09 (m, 2H), 4.39 (s, 2H). ESHRMS m/z 319.9981 (M+H, C₁₅H₁₁ClNOS₂requires 319.9971).

Anal. Calc'd for C₁₅H₁₀ClNOS₂: C, 56.33; H, 3.15; N, 4.38. Found: C,56.47; H, 3.13; N, 4.44.

EXAMPLE 3

Prepared by the method described in Example 1, steps 1 and 2. mp164.0-165.0° C. ¹H NMR (acetone-d₆/300 MHz) 8.49 (m, 2H), 7.25 (m, 2H),7.0 (m, 3H), 4.38 (s, 2H), 2.24 (s, 3H). ESHRMS m/z 334.0130 (M+H,C₁₆H₁₂ClNOS₂ requires 334.0127).

Anal. calc'd for C₁₆H₁₂ClNOS₂: C, 57.56; H, 3.62; N, 4.20. Found: C,57.68; H, 3.67; N, 4.17.

EXAMPLE 4

Prepared by the method described in Example 1, steps 1 and 2. mp126.5-126.6° C. ¹H NMR (acetone-d₆/300 MHz) 8.40 (m, 2H), 7.17 (m, 2H),7.0 (m, 4H), 4.39 (s, 2H), 2.85 (s, 3H). ESHRMS m/z 300.0483 (M+H,C₁₆H₁₄NOS₂ requires 300.0517).

Anal. Calc'd for C₁₆H₁₃NOS₂: C, 64.18; H, 4.38; N, 4.68. Found: C,64.05; H, 4.27; N, 4.59.

EXAMPLE 5

Prepared by the method described in Example 1, steps 1 and 2. mp159.6-159.7° C. ¹H NMR (acetone-d₆/300 MHz) 8.52 (m, 2H), 7.6 (m, 1H),7.50 (s, 1H), 7.21 (m, 2H), 7.13 (m, 2H), 4.40 (s, 2H). ESHRMS m/z363.9503 (M+H, C₁₅H₁₁BrNOS₂ requires 363.9465).

Anal. Calc'd for C₁₅H₁₀BrNOS₂: C, 49.46; H, 2.77; N, 3.84. Found: C,49.51; H, 2.68; N, 3.74.

EXAMPLE 6

Prepared by the method described in Example 1, steps 1 and 2. mp198.8-198.9° C. ¹H NMR (acetone-d₆/300 MHz) 8.45 (m, 2H), 7.05 (m, 3H),6.95 (m, 1H), 6.82 (m, 1H), 4.29 (s, 2H), 2.14 (s, 3H), 2.08 (s, 3H).ESHRMS m/z 314.0691 (M+H, C₁₇H₁₆NOS₂ requires 314.0673).

EXAMPLE 7

Prepared by the method described in Example 1, steps 1 and 2. mp182.6-183.0° C. ¹H NMR (acetone-d₆/300 MHz) 8.50 (m, 2H), 7.42 (d, 2H,J=8.5 Hz), 7.23 (d, 2H, J=8.5 Hz, 7.10 (m, 2H), 4.40 (s, 2H). ESHRMS m/z370.0173 (M+H, C₁₆H₁₁F₃NO₂S₂ requires 370.0183).

EXAMPLE 8

Prepared by the method described in Example 1, steps 1 and 2. mp193.3-193.4° C. ¹H NMR (acetone-d₆/300 MHz) 8.49 (m, 2H), 7.69 (d, 2H,J=8.2 Hz), 7.46 (d, 2H, J=8.2 Hz), 7.01 (m, 2H), 4.43 (s, 2H). ESHRMSm/z 311.0327 (M+H, C₁₆H₁₁N₂OS₂ requires 311.0313).

EXAMPLE 9

Prepared by the method described in Example 1, steps 1 and 2. mp191.5-192.5° C. ¹H NMR (CDCl₃/300 MHz) 8.55 (dd, 2H, J=4.6, 1.6 Hz), 7.4(m, 1H), 7.09-7.03 (m, 3H), 6.67 (d, 1H, J=8.7 Hz), 4.17 (s, 2H), 3.86(s, 3H). ESHRMS m/z 350.0090 (M+H, C₁₆H₁₃ClNO₂S₂ requires 350.0076).

Anal. Calc'd. for C₁₆H₁₂ClNO₂S₂: C, 54.93; H, 3.60; N, 4.00; Cl, 10.13;S, 18.33. Found: C, 54.74; H, 3.60; N, 3.89; Cl, 10.45; S, 18.32.

EXAMPLE 10

Prepared by the method described in Example 1, steps 1 and 2. mp172.1-173.1° C. ¹H NMR (CDCl₃/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz),7.23-7.21 (m, 4H), 7.04 (dd, 2H, J=4.6, 1.6 Hz), 4.17 (s, 2H), 1.25 (s,9H). ESHRMS m/z 342.1004 (M+H, C₁₉H₂₀NOS₂ requires 342.0986).

Anal. Calc'd for C₁₉H₁₉NOS₂: C, 66.83; H, 5.61; N, 4.10; S, 18.78.Found: C, 66.97; H, 5.89; N, 4.02; S, 18.64.

EXAMPLE 11

Prepared by the method described in Example 1, steps 1 and 2. mp203.0-204.1° C. ¹H NMR (CDCl₃/300 MHz) 8.52 (dd, 2H, J=4.4, 1.6 Hz),7.29 (d, 1H, J=6.8 Hz), 7.28 (d, 1H, J=7.0 Hz), 7.05 (dd, 2H, J=4.4, 1.6Hz), 6.70 (d, 1H, J=6.8 Hz), 6.69 (d, 1H, J=6.8 Hz), 4.17 (s, 2H), 3.79(s, 3H). ESHRMS m/z 316.0475 (M+H, C₁₆H₁₄NO₂S₂ requires 316.0466).

Anal. Calc'd. for C₁₆H₁₃NO₂S₂: C, 60.93; H, 4.15; N, 4.44; S, 20.33.Found: C, 60.46; H, 4.17; N, 4.37; S, 19.84.

EXAMPLE 12

Prepared by the method described in Example 1, steps 1 and 2. mp209.1-215.1° C. ¹H NMR (CDCl₃/300 MHz) 8.50 (dd, 2H, J=4.4, 1.6 Hz),7.20 (d, 2H, J=8.0 Hz), 7.03-6.99 (m, 4H), 4.18 (s, 2H), 2.30 (s, 3H).ESHRMS m/z 300.0517 (M+H, C₁₆H₁₄NOS₂ requires 300.0517).

Anal. Calc'd. for C₁₆H₁₃NOS₂: C64.18; H, 4.38; N, 4.69; S, 21.42. Found:C, 64.02; H, 4.62; N, 4.54; S, 21.24.

EXAMPLE 13

Prepared by the method described in Example 1, steps 1 and 2. mp257.6-257.7° C. ¹H NMR (CDCl₃/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz),7.57 (d, 2H, J=8.5 Hz), 7.27-6.99 (m, 4H), 4.18 (s, 2H). ESHRMS m/z411.9348 (M+H, C₁₅H₁₁NIOS₂ requires 411.9327).

Anal. Calc'd. for C₁₅H₁₀NIOS₂: C, 43.81; H, 2.45; N, 3.41. Found: C,43.71; H, 2.27; N, 3.41.

EXAMPLE 14

Prepared by the method described in Example 1, steps 1 and 2. mp197.3-202.2° C. ¹H NMR (CDCl₃/300 MHz) 8.53(dd, 2H, J=4.4, 1.6 Hz), 7.26(d, 2H, J=9.3 Hz), 7.09 (dd, 2H, J=4.4, 1.6 Hz), 6.43 (d, 2H, J=9.3 Hz),4.14 (s, 2H), 2.97 (s, 6H). ESHRMS m/z 329.0789 (M+H, C₁₇H₁₇N₂OS₂requires 329.0782).

Anal. Calc'd. for C₁₇H₁₆N₂OS₂: C, 62.17; H, 4.91; N, 8.53; S, 19.53.Found: C, 61.93; H, 5.12; N, 8.46; S,19.26.

EXAMPLE 15

Prepared by the method described in Example 1, steps 1 and 2. mp176.6-176.7° C. ¹H NMR (CDCl₃/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz),7.29-7.22 (m, 4H), 7.03 (dd, 2H, J=4.4, 1.6 Hz), 6.64 (dd, 1H, J=17.5,10.9 Hz), 5.76 (d, 1H, J=17.7 Hz), 5.31 (d, 1H, J=10.9 Hz), 4.19 (s,2H). ESHRMS 312.0513 (M+H, C₁₇H₁₄NOS₂ requires 312.0517).

Anal. Calc'd. for C₁₇H₁₃NOS₂: C, 65.56; H, 4.21; N, 4.50. Found: C,65.75; H, 4.11; N, 4.46.

EXAMPLE 16

Prepared by the method described in Example 1, steps 1 and 2. mp174.8-175.0° C. ¹H NMR (CDCl₃/300 MHz) 8.50 (dd, 2H, J=4.4, 1.6 Hz),7.23-7.20 (m, 4H), 7.03 (dd, 2H, J=4.6, 1.6 Hz), 4.17 (s, 2H), 2.59 (q,2H, J=7.6 Hz), 1.17 (t, 3H, J=7.7 Hz). ESHRMS m/z 314.0677 (M+H,C₁₇H₁₆NOS₂ requires 314.0673).

Anal. Calc'd. for C₁₇H₁₅NOS₂: C, 65.14; H, 4.82; N, 4.47. Found: C,64.90; H, 4.62; N, 4.45.

EXAMPLE 17

Prepared by the method described in Example 1, steps 1 and 2. mp167.1-167.5° C. ¹H NMR (CDCl₃/300 MHz) 8.52 (dd, 1H, J=4.4, 1.6 Hz),7.33 (d, 1H, J=8.3 Hz), 7.02-7.00 (m, 3H), 6.87-6.83 (m, 1H), 4.19 (s,2H), 2.28 (s, 3H). ESHRMS m/z 379.9577 (M+H, C₁₆H₁₃BrNOS₂ requires379.9622).

Anal. Calc'd. for C₁₆H₁₂BrNOS₂: C, 50.80; H, 3.20; N, 3.70. Found: C,50.69; H, 3.19; N, 3.71.

EXAMPLE 18

Prepared from Example 3 by the method described in Example 1, steps 3and 4. mp 236.7-239.3° C. ¹H NMR (DMSO-d₆/300 MHz) 12.6 (brs, 1H), 8.45(m, 2H), 7.41 (m, 1H), 7.26 (m, 3H), 7.0 (m, 1H), 2.86 (m, 4H), 2.35 (m,4H), 2.27 (s, 3H), 2.16 (s, 3H). ESHRMS m/z 368.4653 (M+H, C₂₀H₂₃ClN₅requires 368.1642).

EXAMPLE 19

Prepared from Example 4 by the method described in Example 1, steps 3and 4. mp 244.0-244.2° C. ¹H NMR (acetone-d₆/300 MHz) 11.6 (brs, 1H),8.35 (m, 2H), 7.35 (m, 2H), 7.25 (m, 4H), 3.05 (m, 4H), 2.47 (m, 4H),2.25 (s, 3H), 2.00 (s, 3H) ESHRMS m/z 334.2018 (M+H, C₂₀H₂₄N₅ requires334.2032).

Anal. Calc'd for C₂₀H₂₃N₅: C, 72.04; H, 6.95; N, 21.00. Found: C, 72.03;H, 7.00; N, 20.85.

EXAMPLE 20

Prepared from Example 5 by the method described in Example 1, steps 3and 4. mp 222.5-223.4° C. ¹H NMR (acetone-d₆/300 MHz) 11.8 (brs, 1H),8.51 (m, 2H), 7.55 (m, 2H), 7.34 (m, 4H), 3.0 (m, 4H), 2.41 (m, 4H),2.22 (s, 3H). ESHRMS m/z 398.0982 (M+H, C₁₉H₂₁BrN₅ requires 398.0980).

EXAMPLE 21

Prepared from Example 6 by the method described in Example 1, steps 3and 4. mp 270.9-272.7° C. ¹H NMR (DMSO-d₆/300 MHz) 12.5 (brs, 1H), 8.41(m, 2H), 7.24 (m, 2H), 7.26 (m, 3H), 7.10 (m, 2H), 6.92 (m, 1H), 2.86(m, 4H), 2.38 (m, 4H), 2.21 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H). ESHRMSm/z 348.2183 (M+H, C₂₂H₂₅N₅ requires 348.2188).

EXAMPLE 22

Prepared from Example 7 by the method described in Example 1, steps 3and 4. mp 221.0-221.2° C. ¹H NMR (DMSO-d₆/300 MHz) 12.7 (brs, 1H), 8.45(m, 2H), 7.38 (s, 4H), 7.24 (m, 2H), 2.86 (m, 4H), 2.34 (m, 4H), 2.16(s, 3H). ESHRMS m/z 404.1698 (M+H, C₂₀H₂₁F₃N₅O requires 404.1698).

EXAMPLE 23

Prepared from Example 8 by the method described in Example 1, steps 3and 4. mp >300° C. ¹H NMR (DMSO-d₆/300 MHz) 12.8 (brs, 1H), 8.47 (m,2H), 7.83 (m, 2H), 7.42 (m, 2H), 2.88 (m, 4H), 2.39 (m, 4H), 2.20 (s,3H). ESHRMS m/z 345.1848 (M+H, C₂₀H₂₁N₆ requires 345.1828).

EXAMPLE 24

Prepared from Example 9 by the method described in Example 1, steps 3and 4. mp 272.7-276.4° C. ¹H NMR (DMSO-d₆/300 MHz) 8.44 (dd, 2H, J=4.6,1.6 Hz), 7.32-7.13 (m, 5H), 3.84 (s, 3H), 2.90-2.85 (m, 4H), 2.38-2.35(m, 4H), 2.16 (s, 3H). ESHRMS m/z 384.1580 (M+H C₂₀H₂₃ClN₅O requires384.1591).

EXAMPLE 25

Prepared from Example 10 by the method described in Example 1, 3 and 4.mp 243.6-244.3° C. ¹H NMR (DMSO-d₆/300 MHz) 8.44 (dd, 2H, J=4.6, 1.6,Hz), 7.40 (d, 2H, J=8.3 Hz), 7.28-7.18 (m, 4H), 2.90-2.85 (m, 4=H),2.38-2.34 (m, 4H), 2.16 (s,3H), 1.26 (s, 9H). ESHRMS m/z 376.2491 (M+H,C₂₃H₃₀N₅ requires 376.2501).

EXAMPLE 26

Prepared from Example 11 by the method described in Example 1, steps 3and 4. mp 259.0-260.2° C. ¹H NMR (DMSO-d₆/300 MHz) 8.53 (dd, 2H, J=4.4,1.6 Hz), 7.24 (dd, 2H, J=4.4, 1.6 Hz), 7.18 (d, 2H, J=8.9 Hz), 6.94 (d,2H, J=8.9 Hz), 3.75 (s, 3H), 2.90-2.85 (m, 4H), 2.39-2.35 (m, 4H), 2.16(s, 3H). ESHRMS m/z 350.1991 (M+H, C₂₀H₂₄N₅O requires 350.1981).

Anal. Calc'd. for C₂₀H₂₃N₅O+3.93% H₂O: C, 66.04; H, 6.81; N, 19.25.Found: C, 66.01; H, 6.62; N, 19.32.

EXAMPLE 27

Prepared from Example 12 by the method described in Example 1, steps 3and 4. mp 243.0-246.8° C. ¹H NMR (DMSO-d₆/300 MHz) 8.41 (dd, 2H, J=4.6,1.6 Hz), 7.24 (m, 6H), 2.91-2.86 (m, 4H), 2.40-2.35 (m, 4H), 2.29 (s,3H), 2.16 (s, 3H). ESHRMS m/z 334.2041 (M+H, C₂₀H₂₄N₅ requires334.2032).

Anal. Calc'd for C₂₀H₂₃N₅+4.09% H₂O: C, 69.10; H, 7.13; N, 20.14. Found:C, 69.10; H, 7.08; N, 20.13.

EXAMPLE 28

Prepared from Example 13 by the method described in Example 1, steps 3and 4. mp 265.2-265.8° C. ¹H NMR (CD₃OD/300 MHz) 8.41 (dd, 2H, J=4.6,1.6 Hz), 7.76-7.74 (m, 2H), 7.41-7.39 (m, 2H), 7.08-7.05 (m, 2H),3.08-3.04 (m, 4H), 2.61-2.58 (m, 4H), 2.35 (s, 3H). ESHRMS m/z 446.0847(M+H, C₁₉H₂₁IN₅ requires 446.084169).

Anal. Calc'd. for C₁₉H₂₀IN₅+12.09% H₂O: C, 44.60; H, 5.39; N, 13.69.Found: C, 44.50; H, 4.56; N, 13.66.

EXAMPLE 29

Prepared from Example 15 by the method described in Example 1, steps 3and 4. mp>300° C. ¹H NMR (CD₃OD/300 MHz) 8.49 (dd, 2H, J=4.6, 1.6 Hz),7.47-7.44 (m, 4H), 7.26 (d, 2H, J 8.4 Hz), 6.75 (dd, J=17.7, 11.1 Hz),5.83 (d, 1H, J=17.5 Hz), 5.28 (d, 1H, J=11.1 Hz), 3.07-3.03 (m, 4H),2.58-2.53(m, 4H), 2.31 (s, 3H). ESHRMS m/z 346.2034 (M+H, C₂₁H₂₄N₅requires 346.2032).

Anal. Calc'd. for C₂₁H₂₃N₅+2.83% H₂O: C, 70.95; H, 6.84; N, 19.70.Found: C, 70.97; H, 6.49; N, 19.54.

EXAMPLE 30

Prepared from Example 16 by the method described in Example 1, steps 3and 4. mp 221.6-224.6° C. ¹H NMR (CD₃OD/300 MHz) 8.38 (dd, 2H, J=4.6,1.6 Hz), 7.44-7.40 (m, 2H), 7.26-7.19 (m, 4H), 3.06-3.02 (m, 4H), 2.66(q, 2H, J=7.5 Hz), 2.59-2.54 (m, 4H), 2.32 (s, 3H), 1.23 (t, 3H, J=7.5Hz). ESHRMS m/z 348.2188 (M+H, C₂₁H₂₆N₅ requires 348.2188).

Anal. Calc'd for C₂₁H₂₅N₅+2.59% H₂O: C, 70.71; H, 7.35; N, 19.63. Found:C, 70.76; H, 7.40; N, 19.46.

EXAMPLE 31

Prepared from Example 17 by the method described in Example 1, steps 3and 4. mp 294.7° C. decomp. ¹H NMR (CD₃OD/300 MHz) 8.41 (dd, 2H, J=4.6,1.6 Hz), 7.55 (d, 1H, J=8.2 Hz), 7.45-7.42 (m, 2H), 7.27-7.25 (m, 1H),7.00-6.97 (m 2H), 3.08-3.03 (m, 4H), 2.59-2.54 (m, 4H), 2.35 (s, 3H),2.31 (s, 3H). ESHRMS m/z 412.1124 (M+H, C₂₀H₂₃BrN₅ requires 412.1137).

EXAMPLE 32

To N-(2-hydroxyethyl)morpholine (363 uL, 3 mmol) in anhydrous THF (7mL), under nitrogen, was added 1M sodium bis(trimethylsilyl)amide (3 ml,3 mmol) in THF at ambient temperature. The reaction mixture was stirredfor 15 minutes, then the dithietane of Example 2 (636 mg, 2 mmol) wasadded as a solid. The reaction mixture gradually became dark orange.After about 18 hours at ambient temperature, the reaction was quenchedwith saturated sodium bicarbonate solution (30 mL) and extracted twicewith ethyl acetate (30 mL). The organic solutions were combined andwashed with saturated NaCl solution (20 mL), then dried (MgSO₄),filtered, and concentrated to an orange oil. The oil was taken up inMeOH (10 mL) and reconcentrated to remove any remaining ethyl acetate.The oil was then taken up in methanol (5 mL) and anhydrous hydrazine (69uL) was added. The reaction mixture was allowed to stir at ambienttemperature 18 hours, then quenched with saturated sodium bicarbonatesolution (30 mL) and extracted twice with ethyl acetate (30 mL). Theorganic solutions were combined and washed with water (20 mL) andsaturated NaCl solution (20 mL), then dried (MgSO₄), filtered, andconcentrated to an orange semi-solid. The solid was triturated withacetonitrile (5 mL), collected by suction filtration, washed withacetonitrile and dried in-vacuo. Yield; off-white solid, 114 mg, 14.8%,mp 198.9-199.9° C. ¹H-NMR (DMSO-d₆/300 MHz) 12.61 (br s, 1H), 8.41 (d,2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.21 (d, 2H), 4.33 (t, 2H), 3.54 (m,4H), 2.70 (t, 2H), 2.44 (m 4H). ESHRMS m/z 385.1444 (M+H, C₂₀H₂₂ClN₄O₂requires 385.1431).

EXAMPLE 33

The product was prepared in an analogous manner to that of Example 32,starting with 4-hydroxy-N-t-boc piperidine. Recrystallized fromacetone/methanol. Yield; white solid 263 mg, 29%, mp 230.1-231.8° C.¹H-NMR (DMSOd₆/300 MHz) 12.61 (br s, 1H), 8.42 (d, 2H), 7.52 (d, 2H),7.38 (d, 2H), 7.20 (d, 2H), 4.88 (m, 1H), 3.52 (m, 2H), 3.30 (m, 2H),1.93 (m, 2H), 1.65 (m, 2H), 1.39 (s, 9H).

Anal. Calc'd for C₂₄H₂₇ClN₄O₃: C, 63.36; H, 5.98; N, 12.31. Found: C,63.34; H, 5.97; N, 12.22.

EXAMPLE 34

The product from Example 33 (130 mg, 0.28 mmol) was treated with conc.HCl (0.5 mL) in ethanol (5 mL) for 2 hours. The solvent was removedin-vacuo and the resulting residue dissolved in ethanol andreconcentrated twice. The resulting solid was triturated withacetonitrile to afford a white solid. Yield, 119 mg, 91%,tri-hydrochloride salt, mp 220.6-222.1° C. ¹H-NMR (DMSO-d₆/300 MHz)13.25 (br s, 1H), 9.10 (br s, 2H), 8.67 (d, 2H), 7.75 (d, 2H), 7.60 (d,2H), 7.50 (d, 2H), 5.04 (m, 1H), 3.17 (br d, 4H), 2.21 (m, 2H), 2.03 (m,2H).

Anal. Calc'd for C₁₉H₁₉ClN₄O.3 HCl: C, 49.16; H, 4.78; N, 12.07. Found:C, 49.24; H, 4.72; N, 12.02.

EXAMPLE 35

The product was prepared in a manner analogous to Example 32 startingwith (+/−)3-hydroxytetrahydrofuran. Recrystallized from ethanol. Yield;white crystalline solid, 57 mg, 8%, mp>300° C. ¹H-NMR (DMSO-d₆/300 MHz)12.65 (br s, 1H), 8.42 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.18 (d,2H), 5.28 (m, 1H), 3.86 (m, 2H), 3.82 (m, 1H), 3.75 (m, 1H), 2.26-2.01(br m, 2H).

Anal. Calc'd for C₁₈H₁₆ClN₃O₂: C, 63.25; H, 4.72; N, 12.29. Found: C,63.12; H, 4.51; N, 12.31.

EXAMPLE 36

The product was prepared in a manner analogous to Example 32 startingwith p-methoxybenzyl alcohol. Yield; off-white solid, 252 mg, 21%,mp=229.1-229.2° C. ¹H-NMR (acetone-d₆/300 MHz) 11.62 (br s, 1H), 8.40(br s, 2H), 7.76 (s, 2H), 7.39 (m, 4H), 7.30 (br s, 2H), 6.87 (d, 2H),5.27 (s, 2H), 3.77 (s, 3H).

Anal. Calc'd for C₂₂H₁₈ClN₃O₂.0.25 H₂O: C, 66.67; H, 4.70; N, 10.60.Found: C, 66.79; H, 4.95 ; N, 10.54.

EXAMPLE 37

The product was prepared in a manner analogous to Example 32 startingwith N-Boc-ethanolamine. Recrystallized from ethyl acetate/methanol.Yield; white solid, 75 mg, 4%, mp>300° C. ¹H-NMR (DMSO-d₆/300 MHz) 12.60(br s, 1H), 8.38 (d, 2H), 7.53 (d, 2H), 7.38 (d, 2H), 7.22 (d, 2H), 7.02(t, 1H), 4.20 (t, 2H), 3.34 (m, 2H), 1.36 (s, 9H). ESHRMS m/z 415.1551(M+H, C₂₁H₂₄ClN₄O₃ requires 415.1537).

EXAMPLE 38

The example was prepared in a manner analogous to Example 32 startingwith methanol. Yield; off-white solid, 119 mg, 14%, mp=265.3-265.3° C.¹H-NMR (DMSO-d₆/300 MHz) 12.61 (br s, 1H), 8.41 (d, 2H), 7.52 (d, 2H),7.38 (d, 2H), 7.17 (d, 2H), 3.90 (s, 3H). ESHRMS m/z 286.0766 (M+H,C₁₅H₁₃ClN₃O requires 286.0747).

Anal. Calc'd for C₁₅H₁₂ClN₃O.0.25 H₂O: C, 62.08; H, 4.34; N, 14.48.Found: C, 62.24; H, 4.11; N, 14.16.

EXAMPLE 39

To the dithietane of Example 2 (638 mg, 2 mmol) in toluene (15 mL) wasadded thiomorpholine (800 uL, 8 uL). The reaction mixture was heated toreflux for 6 hours, then cooled to room temperature and diluted withtoluene (20 mL). The reaction mixture was then extracted twice withwater (20 mL) and brine (20 mL). The organic solution was dried (MgSO₄),filtered, and concentrated to an oil. Hexane was added to the residueand heated to reflux, then decanted. The oil became semi-solid. Thesemi-solid was dissolved in tetrahydrofuran (10 mL) and potassiumt-butoxide 1M in THF (2 mL, 2 mmol) was added. This was followed byiodomethane (125 uL, 2 mmol). The reaction was stirred at roomtemperature for 1 hour, then quenched with water (20 mL). The reactionmixture was extracted with ethyl acetate (2×30 mL). The organic layerswere pooled, washed with brine (20 mL) and dried (MgSO₄). Filtration andconcentration produced an oil which was chased once with toluene toremove any ethyl acetate. The residue was dissolved in ethanol (10 mL)and hydrazine hydrate (97 uL, 2 mmol) was added. The reaction mixturewas stirred at room temperature for 4 hours then partitioned betweenethyl acetate and saturated sodium bicarbonate solution (30 mL each).The layers were separated and the aqueous layer extracted again withethyl acetate (30 mL). The combined organic layers were washed withbrine (20 mL) and dried (MgSO₄). Filtration and concentration producedan orange residue which was triturated with acetonitrile to generate atan solid. Yield: 295 mg, 43%, mp>300° C. ¹H NMR (DMSO-d₆/300 MHz) 12.70(br s, 1H), 8.47 (d, 2H), 7.46 (d, 2H), 7.26 (m, 4H), 3.13 (m, 4H), 2.62(m, 4H). ESHRMS m/z 357.0942 (M+H, C₁₈H₁₈ClN₄S requires 357.0941).

Anal. Calc'd for C₁₈H₁₇ClN₄S: C, 60.58; H, 4.80; N, 15.70. Found: C,60.32; H, 4.96; N, 15.60.

EXAMPLE 40

The product of Example 33 (455 mg, 1.5 mmol) was combined with 98%formic acid (6 mL) and heated to 100 C. After 3 hours, 37% formaldehyde(1.22 mL, 15 mmol) was added and the reaction was heated for anadditional 5 hours at 100 C. The reaction mixture was allowed to cool toroom temperature and filtered. The solution was diluted with water (15mL) and extracted once with ethyl acetate (30 mL). The aqueous solutionwas then basified with 2.5 N NaOH to pH 8. The cloudy mixture was thenextracted twice with 1:1 THF:EtOAc (30 mL). The organic layers werepooled and washed once with brine (25 mL), dried (MgSO₄), filtered andconcentrated to an oil which solidified on standing. The solid wastriturated with acetonitrile and collected by suction filtration. Thesolid was suspended in ethanol:water 2:1 (15 mL) and 1 mL of conc. HClwas added. The solution was allowed to stir at room temperature for 1hour, then filtered and concentrated. The residue was combined withethanol (10 mL) and reconcentrated twice. The resulting solid wastriturated with acetonitrile (10 mL) containing a small amount ofethanol (0.5 mL) to remove some colored impurities. The solid wascollected by suction filtration, washed with acetonitrile and driedin-vacuo. Yield: 490 mg ,88%, mp 255.9-256.8° C. ¹H NMR(D₂O/DMSO-d₆/NaOD/300 MHz) 7.93 (d, 2H), 7.09 (s, 4H), 7.00 (d, 2H),4.42 (m, 1H), 2.26 (br m, 2H,) 2.12 (br m, 2H), 1.92 (s, 3H), 1.68 (brm, 2 H), 1.57 (br m , 2H). ESLRMS m/z 369 (M+H).

EXAMPLE 41

Step 1. A mixture of the dithietane from Example 2 (78.3 g, 0.24 mol)and 1-methylpiperazine (75.0 g, 0.73 mol) in 800 mL of toluene washeated to reflux for 2 h. Solvent and excess 1-methylpiperazine wasremoved under vacuum and the residue was triturated with a mixture wasethyl acetate and ether (1:3) to give 53.0 g of product as yellowcrystals ,60%, mp 149-151° C.

Anal. Calc'd. for C₁₉H₂₀ClN₃OS: C, 61.03; H, 5.39; N, 11.24. Found: C,60.74; H, 5.35; N, 11.14.

Step 2. To a suspension of the product from Step 1 (52.0 g, 0.14 mol) in500 mL of dry tetrahydrofuran was added anhydrous hydrazine (8.9 g, 0.28mol) dropwise. The reaction mixture was stirred at room temperature for16 h. The pale yellow precipitate was filtered and recrystallized fromhot methanol to give 30.2 g of the title compound as a white powder,60%, mp 267-268° C.

Anal. Calc'd. for C₁₉H₂₀ClN₅: C, 64.49; H, 5.70; N, 19.79. Found: C,64.89; H, 5.55; N, 19.99.

EXAMPLE 42

To 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (1.0 g, 4.7 mmol), inanhydrous THF (10 mL) was added a solution of 1M potassium t-butoxide inTHF (10 mL, 10 mmol). The reaction mixture was stirred for 15 minutes atroom temperature, then carbon disulfide (0.31 mL, 5.1 mmol) was added.After several minutes, methyl iodide (0.64 mL, 10.3 mmol) was added andthe reaction allowed to stir for 4 hours. The reaction mixture wasdiluted with saturated sodium bicarbonate solution (25 mL) and extractedtwice with ethyl acetate (35 mL). The combined ethyl acetate layers werewashed with water (25 mL) and brine (25 mL). The organic solution wasdried (MgSO₄), filtered and concentrated to an orange oil. The oilsolidified on standing to afford 1.4 g, 94%, of the expected product mp80.2-82.1° C. ¹H-NMR (CDCl₃/300 MHz) 8.59 (d, 2H), 7.96 (m, 2H), 7.38(m, 2H), 7.14 (m, 2H), 2.33 (s, 3H), 2.23 (s, 3H).

Anal. Calc'd for C₁₆H₁₄FNOS₂: C, 60.16; H, 4.42; N, 4.39; S, 20.08.Found: C, 59.89; H, 4.09; N, 4.31; S, 20.14.

EXAMPLE 43

The product was prepared in a manner analogous to Example 42 startingfrom 1-(4-chlorophenyl)-2-(4-pyridyl)ethanone. Crude yield; 100%, mp87.6-88.2° C. ¹H-NMR (CDCl₃/300 MHz) 8.60 (d, 2H), 7.87 (d, 2H), 7.44(d, 2H), 7.37 (m, 2H), 2.33 (s, 3H), 2.22 (s, 3H). ESHRMS m/z 336.0297(M+H, C₁₆H₁₄ClNOS₂ requires 336.0283).

Anal. Calc'd for C₁₆H₁₄ClNOS₂: C, 57.22; H, 4.20; N, 4.17. Found: C,57.44; H, 3.97; N, 4.04.

EXAMPLE 44

To the product of Example 42 (1.4 g, 4.4 mmol) in ethanol (15 mL) wasadded 1M hydrazine in acetic acid (5 mL, 5 mmol). The reaction wasstirred at room temperature for 18 hours. No reaction had occurred, soadditional hydrazine hydrate (1.08 mL, 22 mmol) was added and thereaction heated to reflux for 6 hours. The product began to precipitatefrom the reaction mixture. The reaction was cooled to room temperatureand water was added to precipitate the product. The solid was collectedby suction filtration and air dried to afford the crude desiredpyrazole, 675 mg, 53%. The product was recrystallized from ethanol, 494mg, mp 249.9-249.9° C. ¹H-NMR (DMSO-d₆/300 MHz) 13.51 (br s, 1H), 8.50(d, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.16 (m, 2H), 2.43 (s, 3H). ESHRMSm/z 286.0807 (M+H, C₁₅H₁₃FN₃S requires 286.0814).

Anal. Calc'd for C₁₅H₁₂FN₃S: C, 63.14; H, 4.24; N, 14.73. Found: C,63.01; H, 4.43; N, 14.81.

EXAMPLE 45

The product was made in an analogous manner to Example 44 starting withthe product of Example 43. Yield; 750 mg, 33%, mp 250.2-250.2° C. ¹H NMR(DMSO-d₆/300 MHz) 13.57 (br s, 1H), 8.51 (m, 2H), 7.45 (br s, 2H), 7.32(m, 2H), 7.17 (m, 2H), 2.43 (s, 3H). ESHRMS m/z 302.0537 (M+H,C₁₅H₁₃ClN₃S requires 302.0518).

Anal. Calc'd for C₁₅H₁₂ClN₃S: C, 59.70; H, 4.01; N, 13.92. Found: C,59.56; H, 3.96; N, 13.96.

EXAMPLE 46

To the product of Example 44 (150 mg, 0.52 mmol) in ethanol (15 mL) wasadded ammonium persulfate (450 mg, 1.97 mmol). The reaction mixture wasstirred at ambient temperature. After several hours an additional amountof ammonium persulfate (450 mg) was added. The reaction mixture wasmonitored by TLC (silica) using 5% methanol in dichloromethane as theeluting solvent. When the starting material had been consumed, thereaction mixture was quenched with saturated sodium bicarbonate (25 mL)and extracted with ethyl acetate (2×25 mL). The ethyl acetate layerswere combined, washed with brine (25 mL) and dried (MgSO₄). Filtrationand concentration produced a white solid. The solid was triturated withdiethyl ether, collected by suction filtration, and air dried to provide150 mg, 96%, mp 262.9-262.9° C. of the desired sulfoxide. ¹H NMR(DMSO-d₆/300 MHz) 14.22 (br s, 1H), 8.56 (d, 2H), 7.42-7.23 (br m, 6H),2.94 (s, 3H).

Anal. Calc'd for C₁₅H₁₂FN₃OS.80.25 H₂O: C, 58.91; H, 4.12; N, 13.74.Found: C, 58.88; H, 4.17; N, 13.39.

EXAMPLE 47

To the product of Example 44 (285 mg, 1 mmol) in ethanol (10 mL) wasadded potassium peroxymonosulfate (2.45 g, 4 mmol) and water (5 mL). Thereaction mixture was stirred at ambient temperature. After 6 hours thereaction mixture was diluted with water (20 mL) and extracted with ethylacetate (2×30 mL). The ethyl acetate layers were combined, washed withbrine (25 mL) and dried (MgSO₄). The ethyl acetate did not efficientlyextract the product from the aqueous phase, so the aqueous layer wassaturated with sodium chloride and extracted with acetonitrile (50 mL).The acetonitrile solution was dried (MgSO₄), filtered, and combined withthe filtered ethyl acetate solution. The solvents were evaporated andthe resulting solid was triturated with a small amount of acetonitrile,collected by suction filtration, and air dried to afford 203 mg, 64%, mp297.1→300° C. ¹H NMR (DMSO-d₆/300 MHz) 14.37 (br s, 1H), 8.54 (m, 2H),7.29 (m, 6H), 3.26 (s, 3H).

Anal. Calc'd for C₁₅H₁₂FN₃O₂S: C, 56.77; H, 3.81; N, 13.24. Found: C,56.52; H, 4.03; N, 13.11.

EXAMPLE 48

The product was prepared in a similar manner to Example 1 starting frommethyl 4-bromobenzoate. Obtained a white solid, mp 270.2-270.7° C. ¹ HNMR (DMSO-d₆/300 MHz) 12.7 (br s, 1H), 8.47 (m, 2H), 7.57 (m, 2H), 7.21(m, 2H), 2.85 (m, 4H), 2.34 (m, 4H) 2.15 (s, 3H). ESHRMS 398.0993 (M+H,C₁₉H₂₁BrN₅ requires 398.0980).

EXAMPLE 49

The product from Example 2 (50 g, 0.156 mol) and anhydrous hydrazine (25mL, 0.8 mol) were heated to reflux in ethanol for 5 hours. The contentswere allowed to cool whereupon a precipitate formed that was isolated byfiltration. The solid was air dried to afford the desired product as ayellow-orange solid (21.8 g) The filtrate was diluted with water (200mL) and a second crop was obtained as a yellow-orange solid (18.0 g).The pH of the filtrate was adjusted to pH 8 with 3N HCl and theprecipitated solid filtered to give an additional crop of the desiredproduct as a yellow-orange solid (2.0 g). The combined crops affordedthe desired pyrazole in 93% yield, mp 266.3-268.9° C. ¹H NMR (DMSO-d₆)13.80 (br, 1H); 12.20 (br s, 1H); 8.32 (s, 4H); 7.50-7.30 (m, 4H).ESHRMS m/z 288.0358 (M+H, C₁₄H₁₁ClN₃S requires 288.0362).

Anal. Calc'd for: C₁₄H₁₀ClN₃S (0.4 H₂O): C, 57.01; H, 3.69; N, 14.25.Found: C, 56.95; H, 3.50 N, 14.14.

EXAMPLE 50

The above pyrazole was prepared by the method outlined in Example 49 mp261.3-263.9° C. ¹H NMR (DMSO-d₆) 11.5 (br s, 1H); 8.25-8.13 (m, 2H);7.61-7.50 (m, 2H); 7.36-7.20 (m, 2H); 7.19-7.05 (m, 2H). ESHRMS m/z272.0691 (M+H, C₁₄H₁₁FN₃S requires 272.0657).

Anal. Calc'd for: C₁₄H₁₀FN₃S (0.25 H₂O): C, 60.97; H, 3.84; N, 15.24.Found: C; 61.05; H, 3.64 N, 15.12.

EXAMPLE 51

To the product from Example 49 (100 mg, 0.35 mmol) in methanol (2 mL)was added 0.5 M sodium methoxide (0.7 mL, 0.35 mmol). Contents werestirred for 15 minutes and filtered to remove a precipitate. Thefiltrate was concentrated in vacuo, dissolved in water and concentratedin vacuo leaving the desired product as a white solid. ¹H NMR (DMSO-d₆)11.60 (br s, 1H); 8.20 (d, 2H); 7.60-7.50 (m, 2H); 7.40-7.20 (m, 4H).

Anal. Calc'd for: C₁₄H₉ClN₃NaS (2.5 H₂O): C, 47.40; H, 3.98; N, 11.84.Found: C, 47.39; H, 3.33; N, 11.50.

EXAMPLE 52

To the material prepared in Example 49 (584 mg, 2.0 mmol) andbromoacetonitrile (140 ul, 2.0 mmol) in DMF (5 mL) was added anhydrouspotassium carbonate (276 mg, 2.0 mmol). Contents were stirred overnight,then partitioned between EtOAc and H₂O: The EtOAc layer was dried overMgSO₄ and concentrated in vacuo leaving a tan solid. The solid wastriturated with MeOH and filtered to give the desired product as aoff-white solid, 369 mg, 56%, mp 230.0-230.5° C. ¹H NMR (DMSO-d₆) 13.90(br s, 1H); 8.58 (d, 2H); 7.60-7.13 (m, 6H); 4.10 (s, 2H). ESHRMS m/z327.0482 (M+H, C₁₆H₁₂ClN₄S requires 327.0471).

Anal. Calc'd for: C₁₆H₁₁ClN₄S(0.3 H₂O): C, 57.85, H, 3.52; N, 16.87.Found: C, 57.88; H, 3.31; N, 16.77.

EXAMPLE 53

Prepared by the method described in Example 52, using methylchloroacetate. When the contents were partitioned between EtOAc and H₂O,an insoluble solid was filtered to give the desired product as a whitesolid 2.16 g. A second crop, 1.68 g, of the desired product gave a totalyield of 61%, mp 192.8-195.2° C. ¹H NMR (DMSO-d₆+approx. 10% TFA) 9.80(d, 2H); 7.80 (d, 2H); 7.52-7.34 (m, 4H); 3.92 (s, 2H); 3.57 (s, 3H).ESHRMS m/z 360.05735 (M+H, C₁₇H₁₅ClN₃O₂ requires 360.05732).

Anal. Calc'd for: C₁₇H₁₄ClN₃O₂ (0.25 H₂O): C, 56.05, H, 4.01; N, 11.53.Found: C, 56.10; H, 3.72; N, 11.51.

EXAMPLE 54

The above compound was prepared by heating the product of Example 49(1.2 g, 4.2 mmol), potassium carbonate (630 mg, 4.6 mmol),N-boc-4-bromopiperidine (1.2 g, 4.5 mmol) were heated in DMF (15 mL) at105 C. for 3 hours. Contents were allowed to cool and partitionedbetween EtOAc and water. The EtOAc layer was dried over MgSO₄andconcentrated in vacuo. The residue was triturated with EtOAc andfiltered to give the desired as a white solid 1.20 g, 61%, mp220.9-221.0° C. ¹H NMR (DMSO-d₆) 13.70 (br, 1H), 8.60-8.50 (m, 2H),7.58-7.10 (m, 6H); 3.80-3.60 (m, 2H); 3.40-3.20 (m, 1H); 3.00-2.63 (m,2H); 2.00-1.53 (m, 2H); 1.50-1.05 (m, 2H); 1.40 (s, 9H). FABHRMS m/z471.1605 (M+H, C₂₄H₂₈ClN₄OS requires 471.1622).

Anal. Calc'd for: C₂₄H₂₇ClN₄OS (0.5 H₂O): C, 60.05; H, 5.88; N, 11.67.Found: C, 60.04; H, 5.57; N, 11.31.

EXAMPLE 55

The product from Example 54 (5.0 g, 11 mmol), and TFA (30 mL) were mixedin CH₂Cl₂ (50 mL) and stirred overnight. Contents were concentrated invacuo leaving a pale yellow oil which was dissolved in water. The pH wasadjusted with 2.5 N NaOH to pH 9, causing a white solid to form that wasisolated by filtration to provide the desired product as a white solid,3.7 g, 93%, mp 211.1-211.2° C. ¹H NMR (DMSO-d₆) 13.80 (br, 1H); 8.55 (d,2H); 8.40 (br, 1H); 7.50-7.15 (m, 6H); 3.50-3.00 (m, 3H); 3.00-2.80 (m,2H); 2.05-1.80 (m, 2H); 1.65-1.42 (m, 2H). ESHRMS m/z 371.1103 (M+H,C₁₉H₂₀ClN₄S requires 371.1097).

Anal. Calc'd for: C₁₉H₁₉ClN₄S (H₂O): C, 58.68; H, 5.44; N, 14.41. Found:C, 58.86; H, 5.28; N, 14.25.

EXAMPLE 56

To 1-(2-chloroethyl)pyrrolidine hydrochloride (306 mg, 1.8 mmol) inmethanol (10 mL) was added 0.5 M sodium methoxide (7.0 mL, 3.6 mmol).Contents were stirred 10 minutes and then the material from Example 49(500 mg, 1.8 mmol) were added. Contents were heated to reflux 1 hour,allowed to cool and partitioned between EtOAc and H₂O. The EtOAc layerwas dried over MgSO₄ and concentrated in vacuo leaving a light ambersolid. The solid was recrystallized from MeOH (15 mL) to give thedesired product as a white solid (213 mg, 33% yield). mp 189.9-190.1° C.¹H NMR (DMSO-d₆) 13.65 (br, 1H); 8.52 (d, 2H); 7.42 (d, 2H); 7.38-7.10(m, 4H); 3.10-2.93 (m, 2H); 2.63-2.51 (m, 2H); 2.38 (br, s, 4H);1.70-1.52 (m, 4H). ESHRMS m/z 385.1262 (M+H, C₂₀H₂₂ClN₄ requires385.1254).

Anal. Calc'd for: C₂₀H₂₁ClN₄: C, 62.41, H, 5.50; N, 14.56. Found C,62.22; H, 5.62; N, 14.48.

EXAMPLE 57

Method A. The material prepared in Example 53 (1.3 g, 3.6 mmol) inmethanol (10 mL), 2.5N sodium hydroxide (4 mL) and water (10 mL) werestirred overnight. The contents were concentrated in vacuo to remove themethanol and the aqueous solution left was made acidic to pH 6 with 3NHCl, precipitating a solid. The solid was extracted into EtOAc, driedover MgSO₄ and concentrated in vacuo leaving light tan crystals, 205 mg.Brine was added to the aqueous layer precipitating additional solid thatwas filtered to give more desired product as a light tan powder, 529 mg,the total yield was 61%. ¹H NMR (DMSO-d6+10% TFA) 8.80 (d, 2H); 7.83 (d,2H); 7.55-7.35 (m, 4H); 3.87 (s, 2H);

Method B. The product from Example 53 (3.8 g, 11 mmol) and 3N HCl (30mL) were heated to reflux for 3 hours. Contents were allowed to cool andconcentrated in vacuo. The residue was mixed with CH₃CN (50 mL). Uponstanding overnight, pale yellow crystals grew that were isolated byfiltration to afford the desired product as the HCl salt 2.9 g, 69%. ¹HNMR (DMSO-d₆) 8.79 (d, 2H); 7.75 (d, 2H); 7.51-7.38 (m, 4H); 3.88 (s,2H). ESHRMS m/z 346.0435 (M+H, C₁₇H₁₃ClN₄OS requires 346.0417).

Anal. Calc'd for: C₁₇H₁₂ClN₄OS (HCl, 0.5 H₂O): C, 49.12; H, 3.61; N,10.74. Found: C, 49.36; H, 3.48; N, 10.72.

EXAMPLE 58

The material prepared in Example 53 (400 mg, 11 mmol) and a 2M solutionof methylamine in THF (25 mL) were heated to reflux for 3 hours. Thereaction was stirred overnight at room temperature and then filtered toafford the desired product as a light ambler solid, 335 mg, 85%, mp284.0-288.4° C. ¹H NMR (DMSO-d₆) 13.58 (br, 1H); 8.60-8.45 (m, 2H); 7.98(br s, 1H); 7.55-7.12 (m, 6H); 3.60 (s, 2H); 2.46 (s, 3H). ESHRMS m/z359.0733 (M+H, C₁₇H₁₆ClN₄OS requires 359.0745).

Anal. Calc'd for: C₁₇H₁₅ClN₄OS: C, 56.90; H, 4.21; N, 15.61. Found: C,56.74; H, 4.11; N, 15.17.

EXAMPLE 59

The material prepared in Example 53 (415 mg, 12 mmol) and N,N-dimethylaminopropylamine were heated to reflux in methanol (25 mL) for3 hours. The contents were stirred overnight at room temperature andthen concentrated in vacuo to afford a solid. The solid was trituratedwith EtOAc and filtered to give the desired product as a white solid.256 mg, 50%, mp 168.8-169.5° C. ¹H NMR (DMSO-d₆) 13.80 (br, 1H);8.55-8.50 (m 2H); 8.02 (t, 1H); 7.50-7.40 (m, 6H); 3.61 (s, 2H);3.30-2.98 (m, 2H); 2.14-2.10 (m, 2H); 2.04 (s, 6H); 1.50-1.40 (m, 2H).FABHRMS m/z 430.1472 (M+H, C₂₁H₂₅ClN₅OS requires 430.1468).

Anal. Calc'd for: C₂₁H₂₄ClN₅OS (0.5 H₂O): C, 57.46; H, 5.74; N, 15.95.Found: C, 57.71; H, 5.56; N, 16.12.

EXAMPLE 60

To the material prepared in Example 54 (1.0 g, 2.1 mmol) in CH₂Cl₂ (25mL) was added 3-chloroperbenzoic acid (425 mg, 2.1 mmol). The reactionwas stirred 15 minutes and thee chromatographed on silica gel (20 g)eluting with EtOAc. The desired product crystallized from the collectedfractions and the product was isolated by filtration and air dried togive 958 mg, 93% mp 215.8-215.9° C. ¹H NMR (DMSO-d₆) 14.34 (br s, 1H);8.57-8.54 (m, 2H); 7.51-7.25 (m, 6H); 4.00-3.82 (m, 2H); 3.60-3.40 (m,1H); 2.85-2.70 (m, 2H); 2.10-1.95 (m, 1H); 1.56-1.10 (m, 3H); 1.36 (s,9H). ESHRMS m/z 487.1580 (M+H, C₂₄H₂₈ClN₄O₃S requires 487.1571).

Anal. Calc'd for: C₂₄H₂₇ClN₄O₃S: C, 59.19; H. 5.59; N, 11.50. Found: C,59.00; H. 5.76; N, 11.46.

EXAMPLE 61

To the material prepared in Example 60 (320 mg, 0.68 mmol) in EtOH (5mL) was added an aqueous solution of potassium peroxymonosulfate (420mg, 0.68 mmol). Contents were stirred for 2 hours and extracted intoEtOAc. The extracts were dried over MgSO₄ and concentrated in vacuoleaving a white solid. The solid was triturated with methanol andfiltered to give the desired as a white solid, 90 mg, 26%, mp228.0-230.8° C. ¹H NMR (DMSO-d₆) 8.61 (d, 2H); 7.48 (d, 2H); 7.31-7.20(m, 4H); 4.05-3.90 (m, 2H); 3.54-3.35 (m, 1H); 2.85-2.60 (m, 2H);1.92-1.80 (m, 2H); 1.48-1.25 (m, 2H); 1.32 (s, 9H). ESHRMS m/z 503.1541(M+H, C₂₄H₂₈ClN₄O₄S requires 503.1520).

Anal. Calc'd for: C₂₄H₂₇ClN₄O₄S (H₂O): C, 56.30; H, 5.51; N, 10.94.Found: C, 56.41; H, 5.78; N, 10.54.

EXAMPLE 62

The product from Example 48 was converted to the corresponding sulfoxideby the procedure described Example 60. The crude product was purified byflash chromatography, the solid thus obtained was recrystallized fromacetonitrile to give the desired product as white crystals, 64 mg, 33%,mp 189.5-189.5° C. ¹H NMR (DMSO-d₆) 14.28 (br s, 1H); 8.50 (d, 2H);7.40-7.20 (m, 4H); 7.20-7.05 (m, 4H); 6.85 (d, 2H); 4.41 (s, 2H); 3.70(s, 3H). ESHRMS m/z 408.1168 (M+H, C₂₂H₁₉FN₃O₂S requires 408.1182).

Anal. Calc'd for: C₂₂H₁₈FN₃O₂S: C, 64.85; H, 4.45; N, 10.31. Found: C,64.44; H, 4.34; N, 10.70

EXAMPLE 63

To the material prepared in Example 62 (1.2 g, 2.5 mmol) in CH₂Cl₂ (50mL) was added 3-chloroperbenzoic acid (1.0 g, 5.0 mmol). Contents werestirred 1.5 hours and then filtered to remove a white solid (620 mg).The filtrate was concentrated and the residue chromatographed on silicagel (20 g) eluting with EtOAc to give the desired product as a whitesolid, 98 mg, 9%, mp 241.9-242.0° C. ¹H NMR (DMSO-d₆) 8.48-8.40 (m, 2H);7.33-6.80 (m, 10H); 4.55 (s, 2H); 3.72 (s, 3H). ESHRMS m/z 424.1143(M+H, C₂₂H₁₉FN₃O₃S requires 424.1131).

Anal. Calc'd for: C₂₂H₁₈FN₃O₃S: C, 62.40; H, 4.28; N, 9.92. Found: C,62.14; H, 4.42; N, 9.68.

EXAMPLE 64

The product from Example 54 (5.0 g, 0.01 mol) and formic acid (96%, 7mL) were heated at 100° C. for 1 hour. Contents were allowed to cool toabout 50° C. and added formaldehyde (37%, 13 mL). The reaction washeated at 80° C. for an additional 2 hours, and then allowed to cool,diluted with water (200 mL) and made basic to pH 11 with 2.5N NaOHwhereupon a precipitate formed. The solid was isolated by filtration andrecrystallized from methanol to give the desired product as a whitesolid, 174 mg, 33%, mp 227.7-227.7° C. ¹H NMR (DMSO-d₆) 13.70 (br s,1H); 8.56-8.48 (m, 2H); 7.50-7.15 (m, 6H); 3.10-2.92 (m, 1H); 2.63-2.50(m, 2H); 2.05 (s, 3H); 1.95-1.65 (m, 4H); 1.50-1.30 (m, 2H). ESHRMS m/z385.1233 (M+H, C₂₀H₂₂ClN₄S requires 385.1254).

Anal. Calc'd for: C₂₀H₂₁ClN₄S: C, 62.41; H, 5.50; N, 14.56. Found: C,62.40; H, 5.80; N, 14.61.

EXAMPLE 65

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using bromoethyl methyl ether exceptthat the contents were heated at 70° C. for 1 hour before partitioningbetween EtOAc and H₂O. The crude was recrystallized from MeOH/EtOAc togive the desired product as a white solid, 210 mg, 35%, mp 189.2-190.2°C. ¹H NMR (DMSO-d₆) 8.60-8.45 (m, 2H); 7.60-7.10 (m, 6H); 3.60-2.85 (m,7H). ESHRMS m/z 346.0799) M+H, C₁₇H₁₇ClN₃OS requires 346.0781).

Anal. Calc'd for: C₁₇H₁₆ClN₃OS (H₂O): C, 58.73; H, 4.70; N, 12.09.Found: C, 58.67; H, 4.86; N, 12.03.

EXAMPLE 66

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using 2-chloromethylbenzimidazoleexcept that the contents were heated at 70° C. for 1 hour beforepartitioning between EtOAc and H₂O. An insoluble solid was filtered fromthe two layers and triturated with MeOH to give the desired product as alight amber solid, 292 mg, 40%, mp 257.7-257.7° C. ¹H NMR (DMSO-d₆)13.75 (br s, 1H); 12.30 (br s, 1H); 8.55-8.30 (m, 2H); 7.65-6.90 (m,10H); 4.40 (br s, 2H). FABHRMS m/z 418.0895 (M+H, C₂₂H₁₇ClN₅ requires418.0893).

Anal. Calc'd for: C₂₂H₁₆ClN₅ (0.75 H₂O): C, 61.25; H, 4.09; N, 16.23.Found: C, 61.27; H, 3.90; N, 15.92.

EXAMPLE 67

The above compound was prepared from Example 49 according to theprocedure described in Example 54 usingD,L-alpha-bromo-beta-(4-imidazolyl)propionic acid except that thecontents were heated at 70° C. for 1 hour. The contents contained aninsoluble solid which was diluted with water and the pH was adjustedwith 3N HCl to pH 7. Contents were filtered and triturated with MeOH togive the desired product as a white solid, 1.5 g, 81%, mp 163.0-165.5°C. ¹H NMR (DMSO-d₆+approx. 10% TFA) 8.92 (d, 1H); 8.83-8.75 (m, 2H);7.80 (d, 2H); 7.55-7.30 (m, 5H); 4.20-4.05 (m, 1H); 3.25-3.00 (m, 2H).ESHRMS m/z 426.0799 (M+H, C₂₀H₁₇ClN₅O₂S requires 426.0791).

Anal. Calc'd for: C₂₀H₁₆ClN₅O₂S (1.8 H₂O): C, 52.41 H, 4.31; N, 15.28.Found: C, 52.68; H, 4.58; N, 15.37.

EXAMPLE 68

The above compound was prepared from Example 49 (264 mg, 0.9 mmol)according to the procedure described in Example 54 andalpha-methylenebutyrolactone (0.08 mL, 0.9 mmol) in EtOH was added adrop of triethylamine. Contents were stirred overnight and the resultingsolid was filtered and triturated with MeOH to give the desired productas a pale yellow solid, 181 mg, 51%, mp 224.2-225.9° C. ¹H NMR(DMSO-d₆+approx. 10% TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.53-7.33 (m, 4H);4.30-4.05 (m, 2H); 3.50-3.40 (m, 1H); 3.15-2.90 (m, 2H); 2.32-2.20 (m,1H) 2.10-1.90 (m, 1H). ESHRMS m/z 386.0760 (M+H, C₁₉H₁₇ClN₃O₂S requires386.0730).

Anal. Calc'd for: C₁₉H₁₆ClN₃O₂S: C, 59.14 H, 4.18; N, 10.89. Found: C,58.97; H, 4.21; N, 10.96.

EXAMPLE 69

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using 2-bromomethyl-1,3-dioxolaneexcept that the contents were heated at 80° C. for 2 hours. The reactionwas diluted with water and filtered to give a white solid, 502 mg. Thesolid was recrystallized from EtOH to give the desired product asoff-white crystals, 280 mg, 43%, mp 197.0-198.2° C. ¹H NMR (DMSO-d₆)13.60 (br s, 1H); 8.60-8.45 (m, 2H); 7.60-7.10 (m, 6H); 5.15-4.85 (m,1H); 3.95-3.62 (m, 4H); 3.40-2.95 (m, 2H). ESHRMS m/z 374.0741 (M+H,C₁₈H₁₇ClN₃O₂S requires 374.0730).

Anal. Calc'd for: C₁₈H₁₆ClN₃O₂S: C, 57.83 H, 4.31; N, 11.24. Found: C,57.69; H, 4.41; N, 11.15.

EXAMPLE 70

The above compound was prepared from Example 53 according to theprocedure described in Example 54 using2-(2-bromoethoxy)tetrahydro-2H-pyran except that the contents wereheated at 80° C. for 4 hours. Contents were allowed to cool andpartitioned between EtOAc and water. The EtOAc layer was dried overMgSO₄ and concentrated in vacuo leaving a solid, 737 mg. The solid wasrecrystallized from EtOH to give the desired product as pale yellowcrystals, 281 mg, 39%, mp 163.2-163.5° C. ¹H NMR (DMSO-d₆) 13.80-13.70(m, 1H), 8.60-8.42 (br s, 1H); 7.60-7.10 (m, 6H); 4.60-4.30 (m, 1H);3.90-2.90 (m, 6H); 1.70-1.20 (m, 6H). ESHRMS m/z 416.1200 (M+H,C₂₁H₂₃ClN₃O₂S requires 416.1198).

Anal. Calc'd for: C₂₁H₂₂ClN₃O₂S: C, 60.64 H, 5.33; N, 10.10. Found: C,60.49; H, 5.71; N, 9.96.

EXAMPLE 71

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using 4-bromobutyronitrile except thatthe contents were heated at 55° C. for 1 hour. Contents were dilutedwith water (75 mL) and filtered to give a white solid, 567 mg. The solidwas recrystallized from MeOH to give the desired product as whitecrystals, 333 mg, 54%, mp 216.7-216.9° C. ¹H NMR (DMSO-d₆+approx. 10%TFA) 8.80-8.75 (m, 2H); 7.83-7.75 (m, 2H); 7.50-7.35 (m, 4H); 3.10-3.00(m, 2H); 2.60-2.45 (m, 2H); 1.95-1.80 (m, 2H). ESHRMS m/z 355.0818 (M+H,C₁₈H₁₆ClN₄S C₁₈H₁₆ClN₄S requires 355.0784).

Anal. Calc'd for: C₁₈H₁₅ClN₄S(0.5 H₂O): C, 59.42 H, 4.43; N, 15.40.Found: C, 59.64; H, 4.11; N, 15.44.

EXAMPLE 72

The product from Example 57 (416 mg, 1.1 mmol), morpholine (4 mL),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (481mg, 1.5 mmol) and DMF (10 mL) were stirred at room temperatureovernight. The reaction mixture was diluted with water (75 mL) and theresulting solid isolated by filtration, 363 mg. The crude product wasrecrystallized from EtOH to give the desired product as a white solid,219 mg, 48%, mp 215.4-215.5° C. ¹H NMR (DMSO-d₆) 13.70-13.60 (m, 1H);8.60-8.50 (m, 2H); 7.50-7.10 (m, 6H); 3.93-3.80 (m, 2H); 3.60-3.20 (m,8H). ESHRMS m/z 415.0995 (M+H, C₂₀H₂₀ClN₄O₂S requires 415.1001).

Anal. Calc'd for: C₂₀H₁₉ClN₄O₂S: C, 57.90 H, 4.62; N, 13.50. Found: C,57.87; H, 4.86; N, 13.53.

EXAMPLE 73

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using 2-bromopropionitrile except thatthe reaction was heated at 70° C. for 1 hour. The reaction solution wasdiluted with water (75 mL) and filtered to give an off-white solid, 662mg. The crude product was recrystallized from MeOH to give the desiredproduct as a white solid, 220 mg, 37%, mp 211.1-212.8° C. ¹H NMR(DMSO-d₆+approx. 10% TFA) 8.87-8.80 (m, 2H); 7.90-7.80 (m, 2H);7.55-7.45 (m, 6H); 4.42 (q, 1H); 1.50 (d, 3H). ESHRMS m/z 341.0628 (M+H,C₁₈H₁₄ClN₄S requires 341.0628).

Anal. Calc'd for: C₁₈H₁₃ClN₄S: C, 59.91 H, 3.84; N, 16.44. Found: C,59.64; H, 4.01; N, 16.18.

EXAMPLE 74

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using propargyl bromide. The reactionmixture was diluted with water (75 mL) and filtered to give a paleyellow solid, 577 mg. The solid was triturated with MeOH to give thedesired product as a white solid, 388 mg, 68%, mp 212.7-213.2° C. ¹H NMR(DMSO-d₆+approx. 10% TFA) 8.80 (d, J=6.8 Hz, 2H); 7.82 (d, J=6.8 Hz,2H); 7.50-7.35 (m, 4H); 3.81 (d, J=2.6 Hz, 2H); 3.05 (t, J=2.6 Hz, 1H).ESHRMS m/z 326.0533 (M+H, C₁₇H₁₃ClN₃S requires 326.0519).

Anal. Calc'd for: C₁₇H₁₂ClN₃S (0.2 H₂O): C, 61.98 H, 3.79; N, 12.76.Found: C, 61.89; H, 3.45; N, 12.67.

EXAMPLE 75

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using allyl bromide. The reactionmixture was diluted with water (75 mL) and filtered to give a paleyellow solid, 509 mg. The solid was recrystallized from MeOH to give thedesired product as a pale yellow solid, 187 mg, 33%, mp 207.3-208.1° C.¹H NMR (DMSO-d₆+approx. 10% TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.50-7.30(m, 4H); 5.90-5.70 (m, 1H); 5.10-4.95 (m, 2H); 3.62 (d, 2H). ESHRMS m/z328.0693 (M+H, C₁₇H₁₅ClN₃S requires 328.0675).

Anal. Calc'd for: C₁₇H₁₄ClN₃S (0.1 H₂O): C, 61.94 H, 4.34; N, 12.75.Found: C, 61.83; H, 4.21; N, 12.76.

EXAMPLE 76

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using 2-bromoethylamine hydrochlorideexcept that two equivalents of potassium carbonate were used. Thereaction mixture was diluted with water (75 mL) and filtered to give apale yellow solid, 509 mg. The solid was recrystallized from MeOH togive the desired product as a pale yellow solid, 262 mg, 45%, mp186.8-187.8° C. ¹H NMR (DMSO-d₆+approx. 10% TFA) 8.85-8.75 (m, 2H); 8.90(br s, 2H); 8.85-8.75 (m, 2H); 7.55-7.35 (m, 4H); 3.30-3.00 (m, 4H).ESHRMS m/z 331.0779 (M+H, C₁₆H₁₆ClN₄S requires 331.0784).

Anal. Calc'd for: C₁₆H₁₅ClN₄S (0.5 H₂O): C, 56.55; H, 4.75; N, 16.49.Found: C, 56.28; H, 4.38; N, 16.20.

EXAMPLE 77

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using 3-(2-bromoethyl)indole. Thereaction mixture was diluted with water (75 mL) and filtered to give apale yellow solid, 752 mg. The solid was triturated with MeOH to givethe desired product as a white solid, 682 mg, 91%, mp 211.9-213.2° C. ¹HNMR (DMSO-d₆+approx. 10% TFA) 10.80 (s, 1H); 8.72 (d, 2H); 7.71 (d, 2H);7.55-7.35 (m, 5H); 7.29 (d, 1H); 7.12-6.88 (m, 3H); 3.40-3.30 (m, 2H);3.05-2.95 (m, 2H). ESHRMS m/z 431.1095 (M+H, C₂₄H₂₀ClN₄S requires431.1097).

Anal. Calc'd for: C₂₄H₁₉ClN₄S(0.15 H₂O): C, 66.47 H, 4.49; N, 12.92.Found: C, 66.44; H, 4.51; N, 12.84.

EXAMPLE 78

The product from Example 60 (464 mg, 0.95 mmol) and TFA (8 mL) weremixed in CH₂Cl₂ (10 mL) and stirred overnight. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between ether andwater. The aqueous layer was made basic to pH 10 with 2.5N NaOH andextracted with EtOAc (2×100 mL). Upon standing overnight, a solidprecipitated from the aqueous layer and was filtered to give the desiredproduct as a white solid, 183 mg, 50%, mp 189.1-190.8° C. ¹H NMR(DMSO-d₆+approx. 10% TFA) 8.85 (d, 2H); 8.80-8.60 (m 1H); 8.45-8.25 (m,1H); 7.90 (d, 2H); 7.55-7.30 (m, 4H); 3.65-3.20 (m 3H); 3.10-2.80 (m2H); 2.20-2.00 (m, 1H); 1.90-1.50 (m, 3H). ESHRMS m/z 387.1032 (M+H,C₁₉H₂₀ClN₄OS requires 387.1046).

Anal. Calc'd for: C₁₉H₁₉ClN₄OS.(2 H₂O): C, 53.96 H, 5.48; N, 13.25.Found: C, 53.75; H, 4.99; N, 13.21.

EXAMPLE 79

The above compound was prepared from Example 49 according to theprocedure described in Example 54 using 3-bromopropionitrile. Thereaction mixture was diluted with water (75 mL) and extracted intoEtOAc, which was dried over MgSO₄ and concentrated in vacuo leaving anorange waxy solid, 523 mg. The solid was dissolved in acetonitrile,filtered through a pad of silica gel and eluted with EtOAc to give awhite solid. The solid was triturated with EtOAc and filtered to givethe desired product as a white solid, 76 mg, 13%, mp 205.7-206.5° C. ¹HNMR (DMSO-d₆+approx. 10% TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.55-7.35 (m,4H); 3.30-3.20 (m, 2H); 2.90-2.80 (m, 2H). ESHRMS m/z 341.0639 (M+H,C₁₄H₂₀ClN₄S requires 341.0628).

Anal. Calc'd for: C₁₄H₁₃ClN₄S (0.25 H₂O): C, 59.13 H, 3.94; N, 16.22.Found: C, 59.03; H, 3.93; N, 15.90.

EXAMPLE 80

Prepared by the method described in Example 1, steps 1 and 2. mp168.6-168.7° C. ¹H NMR (CDCl₃/300 MHz) 8.54 (dd, 2H, J=4.6, 1.8 Hz),7.68-7.62 (m 2H), 7.43-7.39 (m, 1H), 7.33-7.28 (m, 1H), 6.99 (dd, 2H,J=4.4, 1.6 Hz), 4.22 (s, 2H). ESHRMS m/z 311.0330 (M+H, C₁₆H₁₀N₂OS₂requires 311.0313).

Anal. Calc'd. for C₁₆H₁₀N₂OS₂: C, 61.91; H, 3.25; N, 9.02. Found: C,61.45; H, 3.18; N, 8.91.

EXAMPLE 81

2-(4-flourophenyl)-4-methythiophenylethanone (1.26 g, 4.84 mmol),potassium carbonate (2.04 g 14.5 mmol), carbon disulfide (1.10 g, 14.5mmol) and dibromomethane (1.10 g, 15.4 mmol) were mixed together inacetone (50 ml) for 12 days. The solution was poured into ethyl acetate(100 mL) and washed with 1N hydrochloric acid. Hexanes (25 mL) wereadded and the solution was washed with brine (2×100 mL). The organicsolution was collected, dried over sodium sulfate and solvent removed atreduced pressure. The product 1 was isolated by crystallization fromethyl acetate and hexanes. 831 mg of yellow crystals were obtained. (49%yield) mp 145.7-145.7° C. 1H NMR (CDCl₃/300 MHz) 7.19-7.24 (m, 2H),7.06-7.11 (m, 2H), 6.60-7.30 (m, 4H), 4.11 (s, 2H), 2.42 (s, 3H). HRMS349.0201 (M+H calcd for C₁₇H₁₄FOS₃ 349.0191).

The dithiatane (613 mg, 1.76 mmol) and anhydrous hydrazine (300 uL) wererefluxed in ethanol (10 mL) for 16 hours. The solution was cooled toroom temperature and poured into ethyl acetate (50 mL). The solution wasextracted with 1 N hydrochloric acid (2×25 mL). Hexanes (10 mL) wereadded and the solution was extracted with brine (2×25 mL), dried oversodium sulfate, and solvent removed at reduced pressure. The product 2was isolated by crystallization from dichloromethane and hexanes. 186 mgof yellow crystals were obtained. (32% yield) mp 142.4-143.4° C. ¹H NMR(CD₃OD/400 MHz) 7.18-7.27 (m, 6H), 7.06-7.10 (m,3H), 2.43 (s, 3H). HRMS317.0586 (M+H, calcd for C₁₆H₁₄FN₂S₂ 317.0582)

The pyrazole 2 (140 mg, 0.44 mmol), potassium carbonate (150 mg, 106mmol) and iodomethane (71 mg, 0.50 mmol) were stirred indimethylformamide (5 mL) at room temperature for 16 h. The solution aspoured into ethyl acetate (40 mL) and washed with 1N hydrochloric acid(2×40 mL). Hexanes (25 mL) were added and the solution was washed withbrine (2×50 mL). The organic solution was collected, dried over sodiumsulfate and solvent removed at reduced pressure. The product (22 mg) wasisolated as a semi solid by preparative thin layer chromatography. (13 %yield) ¹H NMR (CDCl₃/400 MHz) 7.23-7.27 (m, 2H), 7.14-7.22 (m, 2H), 2.46(s, 3H), 2.41 (s, 3H). HRMS 331.0735 (M+H, C₁₇H₁₆FN₂S₂ calcd for331.0739).

EXAMPLE 82

Step 1. Preparation of 1-(4-chlorophenyl)-2-(4-pyrimidyl)ethanone

Lithium bis(trimethylsilyl)amide 1.0 M in THF (4.25 L, 4.25 mol) wascooled to −70° C. with stirring under nitrogen. 4-methylpyrimidine (250g, 2.66 mol) was added followed by Methyl 4-chlorobenzoate (453.2 g,2.66 mol). The cooling bath was removed and the mixture was allowed towarm to room temperature and stir for 16 h. Water (3 L) and ethylacetate (3 L) were added followed by acetic acid (200 mL). The layerswere separated and the organic layer was washed with brine and driedover magnesium sulfate. The mixture was then concentrated to 800 mL andhexanes (250 mL) were added. The product was filtered, washed withhexanes, and air dried to provide a yellow solid. (388.1 g, 64%): mp110.4-110.5° C. ¹H NMR (acetone-d₆/300 MHz) 14.9 (bs, 1H), 8.8 (s, 1H),8.4 (m, 1H), 7.7 (d, 2H, J=8.7 Hz), 7.3 (d, 2H, J=8.7 Hz), 6.9 (m, 1H),5.9 (s, 1H).

Step 2. Preparation of dithietane compound

To a solution of 1-(4-chlorophenyl)-2-(4-pyrimidyl)ethanone (7.0 g, 0.03mol) in a mixture of acetone (200 mL) and dibromomethane,(75 mL) wasadded potassium carbonate (8.3 g, 0.06 mol), followed by the slowaddition of carbon disulfide (2.6 g, 0.033 mol) over 15 minutes. Thereaction mixture was stirred at room temperature for 20 h. Solvent wasremoved and the residue was partitioned between water and methylenechloride. The organic layer was washed with brine, dried over magnesiumsulfate and filtered. The filtrate was concentrated and triturated witha mixture of ethyl acetate/ether/hexane (1:5:5) to give 7.14 g ofproduct as a yellow solid which was used without further purification inthe next step.

Step 3. Preparation of1-[5-(4-chlorophenyl)-4-(4-pyrimidinyl)-1H-pyrazol-3-yl-3,4-dimethylpiperazine

To a suspension of the crude material from Step 2 (4.0 g, 0.013 mol) in30 mL of toluene was added a solution of 2,6-dimethylpiperazine (4.65 g,0.04 mol) in 3 mL of acetonitrile. The reaction mixture was stirred at85° C. for 4 h. After the removal of solvent, the crude material wasdissolved in 100 mL of dry THF and hydrazine (0.83 g, 0.026 mol) wasadded. The mixture was then stirred at room temperature overnight. Thesolvent was removed under vacuum and the residue was purified bychromatography in silica gel (ethyl acetate/methanol, 3:1 to 1:1) toafford 0.75 g of the product as a white solid (13% overall yield), mp:212-214° C.; Anal. Calcd. for C₁₉H₂₁ClN₆: C, 61.87; H, 5.74; N, 22.78.Found: C, 61.59; H, 5.28; N, 22.28.

EXAMPLE 83

A mixture of the dithietane compound from example 2 (6.4 g, 0.02 mol)and 2,6-dimethylpiperazine (6.86 g, 0.06 mol) in 100 mL of toluene washeated at reflux for 2 h. Solvent and excess 2,6-dimethylpiperazine wasremoved under vacuum and the crude was used without purification. Asolution of the above crude and anhydrous hydrazine (1.3 g, 0.04 mol) in100 mL of dry THF was stirred at room temperature overnight. After theremoval of THF, the residue was stirred with a mixture of ethyl acetate(100 mL) and ammonia hydroxide (20 ML) for 1 h. The precipitate wasfiltered and air-dried to give 3.4 g of product as a white solid (46%overall yield), mp: 236-238° C.; Anal. Calcd. for C₂₀H₂₂ClN₅+0.25 H₂O:C, 64.51; H, 6.09; N, 18.81; Cl, 9.52. Found: C, 64.28; H, 5.85; N,18.70; Cl, 9.67.

EXAMPLE 84

Prepared by the method described in Example 1, step 1, using4-methylpyrimidine in place of 4-picoline. ¹H NMR (CDCl₃+TFA/300 MHz)8.96 (s, 1H), 8.10 (d, 1H), 7.88 (d, 2H), 7.36 (d, 2H), 7.09 (d, 1H),6.43 (s, 1H), 2.48 (s, 3H). ESHRMS m/z 213.1003 (M+H, C₁₃H₁₂N₂O requires213.1027).

Anal. Calc'd. for C₁₃H₁₂N₂O: C, 73.56; H, 5.70; N, 13.20. Found: C,73.41; H, 6.04; N, 13.17.

EXAMPLE 85

Prepared by the method described in Example 1, step 2. ¹H NMR (CDCl₃/300MHz) 9.02 (s, 1H), 8.40 (d, 1H), 7.37 (d, 2H), 7.23 (d, 2H), 6.67 (d,1H), 4.24 (s, 2H), 2.33 (s, 3H). ESHRMS m/z 301.0488 (M+H, C₁₅H₁₂N₂OS₂requires 301.0469).

Anal. Calc'd. for C₁₅H₁₂N₂OS₂: C, 59.97; H, 4.03; N, 9.33. Found: C,59.43; H, 3.86; N, 9.14.

EXAMPLE 86

The product was prepared in an analogous manner to that of Example 32,starting with 4-hydroxy-N-t-boc piperidine and the product of Example B.

¹H NMR (DMSO-d₆/300 MHz) 8.85 (s, 1H), 8.66 (d, 1H), 7.68 (d, 1H), 7.37(d, 2H), 7.22 (d, 2H), 4.94 (m, 1H), 3.58 (m, 2H), 2.34 (s, 3H), 1.97(m, 2H), 1.69 (m, 2H), 1.40 (s, 9H). ESHRMS m/z 436.2364 (M+H,C₂₄H₂₉N₅O₃ requires 436.2348).

Anal. Calc'd. for C₂₄H₂₉N₅O₃.0.7 H₂O: C, 64.33; H, 6.84; N, 15.63.Found: C, 64.40; H, 6.79; N, 15.63.

The following abbreviations have the indicated meanings:

Ac = acetyl Boc = tertiary-butyloxycarbonyl CDCl₃ = Chloroform-d DMAP =4-(dimethylamino)pyridine DMF = N,N-dimethylformamide DMSO =dimethylsulfoxide EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride EtOAc = ethyl acetate EtOH = ethanol ESHRMS =electro-spray high resolution mass spectrum ESLRMS = electro-spray lowresolution mass spectrum FABHRMS = fast atom bombardment high resolutionmass spectrum HCl = Hydrochloric Acid H₂O = water HOBt =1-hydroxybenzotriazole KHMDS = Postassium bis(trimethylsilyl)amide MeOH= methanol MgSO₄ = magnesium sulfate NaCl = Sodium Chloride NaHMDS =Sodium bis(trimethylsilyl)amide NaOH = Sodium Hydroxide NMR = nuclearmagnetic resonance spectroscopy TBTU =O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium terafluoroborate TFA =trifluoroacetic acid THF = tetrahydrofuran TLC = Thin LayerChromatography

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

We claim:
 1. A process for making a compound or a salt thereof, wherein:the compound corresponds in structure to a formula selected from thegroup consisting of the following:

R₁ is selected from the group consisting of hydrogen, alkyl, alkoxy,cycloalkyloxy, cycloalkyl, cycloalkenyl, 5- or 6-member heterocyclyl,and phenyl, wherein: the heterocyclyl is substituted with one or moresubstituents independently selected from the group consisting of alkyl,halo, hydroxy, alkoxy, cyano, trifluoromethyl, and trifluoromethoxy, andthe phenyl is optionally substituted with one or more substituentsindependently selected from the group consisting of halo, alkoxy,alkylthio, cyano, trifluoromethyl, trifluoromethoxy, alkyl,methylsulfonyl, aminosulfonyl, alkylcarbonylaminosulfonyl, alkenyl, andalkynyl; and R₂ is selected from the group consisting of pyridyl,pyrimidyl, triazinyl, hydrogen, halo, alkyl, 6-member heterocyclyl, andphenyl, wherein: the heterocyclyl and phenyl are optionally substitutedwith up to 2 substituents independently selected from the groupconsisting of halo, alkoxy, alkylthio, cyano, trifluoromethyl,trifluoromethoxy, alkyl, alkylamino, and dialkylamino; and each R₃ isindependently selected from the group consisting of hydrogen, alkyl, andphenyl, wherein: the alkyl and phenyl optionally are substituted withone or more substituents independently selected from the groupconsisting of methylsulfonyl, halo, alkyl, alkoxy, alkylthio, cyano,trifluoromethyl, trifluoromethoxy, and aminosulfonyl; and R₆ is selectedfrom the group consisting of the following:

 the process comprises: reacting an organometallic reagent of theformula R₂CH₂M with an activated form of a carboxylic acid to produce aketone corresponding in structure to Formula IIIc:

 treating the ketone of Formula IIIc with a mixture of carbon disulfideand dihalomethane in the presence of a base and a solvent to produce adithietane derivative corresponding in structure to Formula IIId:

 reacting the dithietane derivative of Formula IIId with R₃NHNH₂ toproduce a heterocycle corresponding in structure to a formula selectedfrom the group consisting of the following:

 reacting the heterocycle of formula IIIe or IIIf with an activated formof R₆ in the presence of a base and a solvent; and M is selected fromthe group consisting of Li, Na, K, and Mg.
 2. The process according toclaim 1, wherein the compound corresponds in structure to the followingformula:


3. The process according to claim 1, wherein the compound corresponds instructure to the following formula:


4. The process according to claim 1, wherein the compound corresponds instructure to the following formula:


5. The process according to claim 1, wherein the compound corresponds instructure to the following formula:


6. The process according to claim 1, wherein the compound corresponds instructure to the following formula:


7. The process according to claim 1, wherein the compound corresponds instructure to the following formula:


8. The process according to claim 1, wherein the compound corresponds instructure to the following formula:


9. A process for making a compound or a salt thereof, wherein: thecompound corresponds in structure to a formula selected from the groupconsisting of the following:

R₁ is selected from the group consisting of hydrogen, alkyl, alkoxy,cycloalkyloxy, cycloalkyl, cycloalkyl, 5- to 6-member heterocyclyl, andphenyl, wherein: the heterocyclyl is substituted with one or moresubstituents independently selected from the group consisting of alkyl,halo, hydroxy, alkoxy, cyano, trifluoromethyl, and trifluoromethoxy, andthe phenyl is optionally substituted with one ore more substituentsindependently selected from the group consisting of halo, alkoxy,alkylthio, cyano, trifluoromethyl, trifluoromethoxy, alkyl,methylsulfonyl, aminosulfonyl, alkylcarbonylaminosulfonyl, alkenyl, andalkynyl; and R₂ is selected from the group consisting of pyridyl,pyrimidyl, triazinyl, hydrogen, halo, alkyl, 6-member heterocyclyl, andphenyl, wherein: the heterocyclyl and phenyl are optionally substitutedwith up to 2 substituents independently selected from the groupconsisting of halo, alkoxy, alkylthio, cyano, trifluoromethyl,trifluoromethoxy, alkyl, alkylamino, and dialkylamino; and each R₃ isindependently selected from the group consisting of hydrogen, alkyl, andphenyl, wherein: the alkyl and phenyl optionally are substituted withone or more substituents independently selected from the groupconsisting of methylsulfonyl, halo, alkyl, alkoxy, alkylthio, cyano,trifluoromethyl, trifluoromethoxy, and aminosulfonyl; and R₆ is selectedfrom the group consisting of the following:

 the process comprises: reacting an organometallic reagent of theformula R₂CH₂M with an activated form of a carboxylic acid to produce aketone corresponding in structure to Formula IIIc:

 treating the ketone of Formula IIIc with a mixture of carbon disulfideand dihalomethane in the presence of a base and a solvent to produce adithietane derivative corresponding in structure to Formula IIId:

 reacting the dithietane derivative of Formula IIId with R₃NHNH₂ toproduce a heterocycle corresponding in structure to a formula selectedfrom the group consisting of the following:

 reacting the heterocycle of formula IIIe or IIIf with an activated formof R₆ in the presence of a base and a solvent; and M is selected fromthe group consisting of Li, Na, K, and Mg.
 10. The process according toclaim 9, wherein R₆ is selected from the group consisting of thefollowing:


11. The process according to claim 10, wherein the compound correspondsin structure to the following formula:


12. The process according to claim 10, wherein the compound correspondsin structure to the following formula:


13. The process according to claim 10, wherein the compound correspondsin structure to the following formula:


14. The process according to claim 10, wherein the compound correspondsin structure to the following formula:


15. The process according to claim 10, wherein the compound correspondsin structure to the following formula:


16. The process according to claim 10, wherein the compound correspondsin structure to the following formula:


17. The process according to claim 10, wherein the compound correspondsin structure to the following formula:


18. The process according to claim 10, wherein the compound correspondsin structure to the following formula:


19. The process according to claim 9, wherein R₆ is selected from thegroup consisting of the following:


20. The process according to claim 19, wherein the compound correspondsin structure to the following formula:


21. The process according to claim 19, wherein the compound correspondsin structure to the following formula:


22. The process according to claim 19, wherein the compound correspondsin structure to the following formula:


23. The process according to claim 19, wherein the compound correspondsin structure to the following formula:


24. The process according to claim 19, wherein R₆ is selected from thegroup consisting of the following:


25. The process according to claim 24, wherein the compound correspondsin structure to the following formula:


26. The process according to claim 24, wherein the compound correspondsin structure to the following formula:


27. The process according to claim 9, wherein R₆ is selected from thegroup consisting of the following:


28. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


29. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


30. The process according to the claim 27, wherein the compoundcorresponds in structure to the following formula:


31. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


32. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


33. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


34. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


35. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


36. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


37. The process according to claim 27, wherein the compound correspondsin structure to the following formula:


38. The process according to claim 27, wherein the compound correspondsin structure to the following formula: